No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.GJB2 encodes connexin 26, a member of the gap junction protein family. Connexins assemble into hexameric channels in the plasma membrane that regulate the passage of ions and small molecules between cells and, when joined between adjacent cells, form intercellular gap junction channels that allow direct cell-to-cell communication. Mutations in this gene are responsible for up to 50% of pre-lingual, recessive deafness. No established role in cancer is described.
The recorded framework is ClinGen GJB2 VCEP v2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
Met (Supporting): SpliceAI predicts no splicing impact (max delta 0.00), satisfying BP4's no-impact clause. Flagged for human review: MaxEntScan was not available, so SpliceAI was used for the BP4 splicing sub-path.
Only BP4 (Supporting) was met, via SpliceAI's no-splicing-impact result (max delta 0.00; REVEL 0.499 uninformative); no other criteria were met, and the variant is classified VUS. The Hearing Loss VCEP v2.0 defines no combination framework, so generic ACMG/AMP 2015 rules were applied.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 84 / 1,613,980 alleles. Recorded AF 5.20453e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 5.66552e-05; MAF= 0.00567%, 16/282410 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138389; MAF= 0.01384%, 1/7226 alleles, homozygotes = 0); grpmax FAF= 6.029e-05.
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.499. Refer to the recorded PP3/BP4 rationale for interpretation.
8 Uncertain significance · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen GJB2 VCEP v2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 6 not met · 12 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Governing framework: ClinGen Hearing Loss Expert Panel Specifications v2.0 (CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA, USH2A) was checked first and used for PP2 and BP1, both of which are explicitly Not Applicable for GJB2 in this specification.
PM1 has a GJB2-panel-wide VCEP document but the only defined PM1 rule is scoped exclusively to KCNQ4 residues 271-292; no GJB2-specific hotspot/domain rule exists, and no domain constraint data was available to support a generic ACMG PM1 argument for transmembrane domain 3 residue 149, so PM1 is not_assessed.
PS1 and PM5 follow unmodified generic ACMG/SVI logic under this VCEP (no GJB2-specific modification noted). No alternate-nucleotide-same-amino-acid comparator (for PS1) or alternate-pathogenic-missense-at-codon-149 comparator (for PM5) was found in the evidence bundle; the dedicated PM5 comparator search failed with an HTTP 429 error before returning results. Both are reported not_assessed with the search/data gap flagged for human review.
No published functional assay (electrical coupling or dye transfer, per GJB2-specific VCEP guidance) was located for NM_004004.6:c.445G>A / NP_003995.2:p.(A149T) in any reviewed full-text source.
Multiple case-report/cohort papers explicitly note the variant was not functionally characterized and state that functional studies would be required to establish pathogenicity.
Two PS3-theme-flagged PMIDs (11445873, 33297549) lack retrieved full text in this case bundle; their titles suggest population/NGS-panel studies rather than functional work, but this could not be confirmed, so PS3/BS3 are returned as not_assessed pending full-text retrieval rather than assumed absent.
Governing framework: ClinGen Hearing Loss VCEP specification to ACMG/AMP (cspec v2.0), which explicitly defines PP3/BP4 rules for GJB2 using REVEL (missense) and MaxEntScan (splicing) at Supporting strength only.
NM_004004.6:c.445G>A (p.Ala149Thr) is a missense variant in the single coding exon of GJB2, not a canonical splice-site or splice-region variant.
REVEL score = 0.499 is intermediate, meeting neither the PP3 (>=0.7) nor the BP4 (<=0.15) missense threshold, so it is uninformative on its own for either criterion.
SpliceAI Lookup (max delta score = 0.00) was used in place of the VCEP-named MaxEntScan tool (unavailable in this case's evidence) to evaluate the splicing sub-path shared by both PP3 and BP4; the result shows no predicted splice impact, supporting BP4 (not PP3).
BayesDel and REVEL are not double-counted; only one code (PP3 or BP4, never both) is applied per the VCEP's own caveat that in silico algorithms sharing similar inputs should not be counted as independent evidence.
BayesDel score was retrieved but excluded from consideration for either criterion because no verified published calibration threshold/PMID exists for this pipeline's BayesDel implementation.
Population evidence does not meet BA1, BS1, BS2, or PM2 under the applicable GJB2 VCEP thresholds; the aggregate gnomAD rarity signal is offset by an ancestry-specific gnomAD v4.1 frequency above the PM2 cutoff.
No criteria match.
The GJB2 VCEP BP4 rule (cspec v2.0) awards BP4_Supporting when 'REVEL score <=0.15 or no impact to splicing in MaxEntScan.' REVEL for this variant is 0.499, which does not meet the <=0.15 BP4 threshold (nor the >=0.7 PP3 threshold), so the missense-score sub-path is neutral/uninformative. The splice sub-path was assessed with the pipeline's available splice predictor, SpliceAI Lookup (max delta score = 0.00; no native site disruption, no cryptic site creation predicted), satisfying the 'no impact to splicing' clause of the VCEP's BP4 rule even though the VCEP names MaxEntScan specifically and no MaxEntScan output exists in this case. Given the SpliceAI result is unambiguous (delta = 0.00 across donor/acceptor gain/loss proxies) and c.445G>A lies deep within the coding exon with no proximity to splice consensus sequences, BP4_Supporting is applied on the splicing sub-path. Flagged for human review because the VCEP's named tool (MaxEntScan) was not available and SpliceAI was substituted.
cspec_v2.0_GJB2_BP4
PM2 is not met under a conservative application of the GJB2 ClinGen Hearing Loss VCEP threshold to the highest observed ancestry-specific allele frequency. For autosomal recessive disease, PM2 supporting requires absence or AF <=0.00007 (0.007%). Although aggregate AF and gnomAD group-max FAF are below the cutoff, gnomAD v4.1 reports a Middle Eastern subgroup AF of 0.000328731 (2/6,084 alleles), which exceeds 0.00007. Because an ancestry-specific frequency exceeds the specified threshold, rarity is not sufficient to apply PM2; no dataset reports homozygotes.
Absent/Rare in population databases (absent or <=0.00007 (0.007%) for autosomal recessive, <=0.00002 (0.002%) for autosomal dominant). PM2 is applied at Supporting strength only under this framework.
GJB2 is governed by the ClinGen Hearing Loss VCEP (cspec v2.0), which specifies for PP3: award if REVEL score >=0.7, OR if splicing is predicted to be impacted (creation of a cryptic splice site or disruption of a native splice site). NM_004004.6:c.445G>A (p.Ala149Thr) is a missense substitution deep within the single coding exon (exon 2) of GJB2, not a splice-region variant. Local REVEL lookup gives a score of 0.499 (prefetch.json/source_registry.json), well below the VCEP's 0.7 PP3 threshold, so the missense sub-path does not support PP3. The splice sub-path was assessed using the pipeline's SpliceAI Lookup screen (source_registry key 'spliceai'; evidence.json) rather than MaxEntScan (no MaxEntScan output is present in this case bundle), which returned a maximum delta score of 0.00 -- no predicted disruption of a native site and no predicted cryptic splice site creation. Neither sub-path supports a deleterious computational prediction, so PP3 is not met.
cspec_v2.0_GJB2_PP3
BA1 is not met. GJB2 is specified as autosomal recessive, and the maximum observed population frequency is far below the ClinGen Hearing Loss VCEP BA1 threshold of 0.005 (0.5%). gnomAD v4.1 reports AF 0.0000520453 overall and the highest subpopulation AF is 0.000328731 in the Middle Eastern group; both are below 0.005. gnomAD v2.1 likewise reports AF 0.0000566552 overall and a highest subpopulation AF of 0.000138389.
MAF of >=0.005 (0.5%) for autosomal recessive; MAF of >=0.001 (0.1%) for autosomal dominant.
BS1 is not met. The GJB2 VCEP thresholds are MAF >=0.003 for strong BS1 and MAF >=0.0007 for supporting BS1 in autosomal recessive disease. The highest observed frequency in the available population datasets is 0.000328731 in gnomAD v4.1 Middle Eastern individuals, below even the supporting threshold; the gnomAD v4.1 group-max FAF is 0.00005798.
MAF of >=0.003 (0.3%) for autosomal recessive; MAF of >=0.0002 (0.02%) for autosomal dominant. Likely benign, provided there is no conflicting evidence. Supporting: MAF of >=0.0007 (0.07%) for autosomal recessive. No BS1_Supporting criteria for autosomal dominant.
BS2 is not met. The applicable GJB2 VCEP rule requires observation of the variant biallelic with a known pathogenic variant in controls for a recessive condition, or another control observation inconsistent with disease penetrance. gnomAD v2.1 and v4.1 each report zero homozygotes, and the available literature extraction does not document a biallelic control observation or a control genotype count for this exact variant. Therefore no BS2 evidence is established.
Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance.
The applicable GJB2 specification defines BP2 as observed in trans with a dominant variant or observed in cis with a pathogenic variant, with caution for genes having both dominant and recessive hearing-loss mechanisms. GJB2 is represented in the governing framework here as autosomal recessive, and the reviewed reports provide no confirmed cis configuration with a pathogenic variant and no qualifying trans observation with a dominant variant. Reports of compound heterozygosity with M34T or V153I do not meet the specified BP2 relationship.
ClinGen Hearing Loss Expert Panel Version 2.0 BP2: Supporting when observed in trans with a dominant variant or observed in cis with a pathogenic variant; use with caution for genes associated with both dominant and recessive hearing loss.
The ClinGen Hearing Loss VCEP specification (v2.0) does not add gene-specific modifications to PS1 for GJB2 and defers to generic ACMG/Richards 2015 guidance: PS1 requires an established pathogenic variant producing the identical amino acid change (p.Ala149Thr) via a different nucleotide substitution. No such alternate-codon-change-to-same-amino-acid comparator variant was identified in the assembled evidence bundle (ClinVar record 44751 is for this exact variant itself, and no other nucleotide change resulting in p.(A149T) was reported in any source). No basis to assess whether the DNA change might act through a distinct mechanism (e.g., splicing) since no comparator exists.
ClinGen Hearing Loss VCEP v2.0 PS1: Same amino acid change as an established pathogenic variant; no GJB2-specific modification, generic ACMG/Richards 2015 rule applies.
The GJB2 ClinGen Hearing Loss VCEP framework provides PS2 point-based de novo rules, but the case bundle contains no confirmed maternity/paternity testing, parental genotypes, or documented de novo occurrence for NM_004004.6:c.445G>A (p.Ala149Thr). The reviewed reports describe affected individuals but do not establish a proven or assumed de novo event. Therefore PS2 cannot be applied.
ClinGen Hearing Loss VCEP GJB2 PS2: 4 points for 2 proven de novo occurrences, 2 points for 1 proven occurrence or 2 assumed occurrences, 1 point for 1 proven phenotype-consistent but nonspecific occurrence or 1 assumed occurrence, and 0.5 points for 1 assumed nonspecific occurrence.
The ClinGen Hearing Loss VCEP specification (cspec) allows PS3_Moderate for GJB2 based on validated electrical coupling or dye transfer assays comparing variant to wildtype and negative controls. No such functional assay for NP_003995.2:p.(A149T)/c.445G>A was found in any reviewed source. Four full-text papers were checked (PMID:10982180, PMID:15146474, PMID:16300957, PMID:23073770); each is a clinical mutation-screening/cohort study reporting the variant's occurrence in patients but explicitly states no functional assay was performed for A149T, and PMID:10982180 and PMID:23073770 explicitly note the variant was 'not clearly established as a deafness mutation' and that functional studies 'would be required.' PMID:16300957 performed Xenopus oocyte electrophysiological assays on other GJB2 mutants but did not include c.445G>A/A149T among tested constructs. Two additional papers flagged as PS3 candidates (PMID:11445873, PMID:33297549) have no full text fetched in this case bundle and their titles (population screening / NGS panel implementation) do not suggest functional assay content; without full-text confirmation they cannot be used to support PS3.
GJB2 PS3_Moderate (ClinGen Hearing Loss VCEP v2.0): validated electrical coupling or dye transfer assay showing significantly reduced/different function vs wildtype and comparable to negative control.
PS4 is not met. The Hearing Loss VCEP specification permits statistical case-control enrichment, with non-statistical proband-count thresholds only for autosomal-dominant disease. GJB2-related nonsyndromic deafness is specified here as autosomal recessive. The directly reviewed papers report isolated/limited A149T observations in affected cohorts, but no eligible case-control comparison or aggregate count of independent qualifying probands with interpretable biallelic genotypes.
Hearing Loss VCEP v2.0: Fisher exact or chi-squared analysis must show a statistically significant increase in cases over controls; non-statistical PS4 thresholds are specified only for autosomal-dominant disease.
The ClinGen Hearing Loss VCEP v2.0 PM1 rule is explicitly scoped only to the KCNQ4 pore-forming intramembrane region (amino acids 271-292); the cspec framework text states PM1/PP4 specifications were removed for genes outside the HL VCEP-defined PM1 scope, and no GJB2-specific PM1 hotspot/domain rule is provided. A cancer-hotspot database query for GJB2 A149 returned no result. Literature extracts note p.Ala149Thr lies in transmembrane domain 3 of connexin-26, but no source in this bundle provides domain-level missense constraint data (e.g., absence of benign variation in that domain) needed to apply a generic PM1 mutational-hotspot/functional-domain argument.
ClinGen Hearing Loss VCEP v2.0 PM1: no GJB2-specific rule (Not Applicable at gene level); generic ACMG PM1 (mutational hotspot/well-studied domain without benign variation) considered but insufficient data.
The applicable ClinGen Hearing Loss Expert Panel specification for GJB2 is autosomal recessive and requires a qualifying observation in trans with a pathogenic variant, or the specified homozygous/two-PM2-supporting-variant alternatives. A149T was reported once with no second GJB2 allele identified, and other reports describe A149T with M34T or V153I, but the available reports contain nomenclature discrepancies and do not provide sufficiently reliable, variant-specific confirmation that the target NM_004004.6:c.445G>A allele is in trans with an established pathogenic allele. The available evidence is therefore insufficient to assign PM3 without human confirmation of the exact variant and phase.
ClinGen Hearing Loss Expert Panel Version 2.0 PM3: Very Strong for 4 points from Tables 7a/7b, Strong for 2 points, Moderate for 1 point when detected in trans with a pathogenic variant in a recessive disorder, and Supporting for 0.5 points for two PM2-supporting variants in trans or a homozygous PM2-supporting variant.
The ClinGen HL VCEP v2.0 PM5 rule follows generic ACMG/SVI guidance: missense change at the same codon as one (Moderate) or two-or-more (Strong) other established pathogenic missense variants. A dedicated PM5 comparator search (pm5_candidates.json) was attempted for residue 149 but failed due to an HTTP 429 rate-limit error before any candidates could be harvested (found=false, same_residue_candidates=0, errors: 'HTTP Error 429: Too Many Requests'). No source in the evidence bundle otherwise reports an alternate pathogenic missense change at codon 149 (e.g., A149V, A149G, A149P). Therefore PM5 cannot be adjudicated from available data.
ClinGen Hearing Loss VCEP v2.0 PM5: Moderate for missense change at same codon as another pathogenic missense variant; Strong if at least two other pathogenic missense variants at that codon.
The applicable GJB2 VCEP framework directs PM6 to the PS2 de novo rules. No assumed de novo occurrence is documented for this variant, and the available reports do not provide parental testing or sufficient inheritance information to infer one. PM6 cannot be applied.
ClinGen Hearing Loss VCEP GJB2 PM6: see the PS2 de novo rules; PM6 requires an assumed de novo occurrence without confirmed maternity and paternity.
The GJB2 VCEP specifies PP1 as supporting for segregation in one affected relative, moderate for two, and strong for three affected relatives in recessive disease. The available publications do not provide validated segregation of the exact NM_004004.6:c.445G>A variant through affected relatives. One paper uses c.446G>A rather than c.445G>A and reports familial context, but no variant-specific segregation result; other reports lack family segregation or have incomplete genotypes. PP1 cannot be applied.
ClinGen Hearing Loss VCEP GJB2 PP1: segregation in three affected relatives for strong, two affected relatives for moderate, and one affected relative for supporting strength in recessive disease.
PP4 is not met. The applicable Hearing Loss VCEP specification requires a patient phenotype highly specific for the gene or a fully sequenced relevant gene set. The bundle provides no phenotype for the individual being interpreted and no diagnostic testing context establishing that the hearing-loss phenotype is specific to GJB2 or that a relevant gene set was fully sequenced.
Hearing Loss VCEP v2.0 PP4: patient's phenotype highly specific for gene or fully sequenced gene set.
The ClinGen Hearing Loss VCEP specification (cspec) allows BS3_Supporting for GJB2 based on validated electrical coupling or dye transfer assays showing variant function comparable to wildtype. No such functional assay for NP_003995.2:p.(A149T)/c.445G>A was identified in any reviewed source. The four full-text papers reviewed (PMID:10982180, PMID:15146474, PMID:16300957, PMID:23073770) are clinical/genetic screening studies; none report a dye transfer or electrical coupling result for A149T, and PMID:16300957's oocyte electrophysiology panel did not include this variant.
GJB2 BS3_Supporting (ClinGen Hearing Loss VCEP v2.0): validated electrical coupling or dye transfer assay showing function comparable to wildtype.
The GJB2 VCEP permits BS4 strong for non-segregation but requires a consistent familial hearing-loss phenotype, reliable affected/unaffected assessment, and caution regarding phenocopy, age, severity, audiogram, and penetrance. The bundle contains no validated phenotype-positive/genotype-negative or genotype-positive/phenotype-negative family member for the exact c.445G>A variant. Incomplete second-allele reporting and absence of a reported segregation result do not constitute BS4.
ClinGen Hearing Loss VCEP GJB2 BS4: strong evidence for non-segregation with disease, with required caution regarding phenotype consistency, age, severity, audiogram, penetrance, phenocopy, and confirmation of unaffected status.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_004004.6:c.445G>A in GJB2 is a missense substitution predicted to produce NP_003995.2:p.(Ala149Thr). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_004004.6:c.445G>A in GJB2 is a missense substitution predicted to produce NP_003995.2:p.(Ala149Thr). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
The ClinGen Hearing Loss VCEP v2.0 specification explicitly marks PP2 as 'Not Applicable' for the genes in this specification set (including GJB2). The panel's governing framework is used here in place of generic ACMG/AMP guidance per curation priority rules.
ClinGen Hearing Loss VCEP v2.0: PP2 Not Applicable for GJB2.
PP5 is not applicable under the Hearing Loss VCEP specification. Independently, the exact ClinVar record has no expert-panel submission; its Likely pathogenic assertion is an ordinary laboratory submission and cannot trigger PP5.
Hearing Loss VCEP v2.0: PP5 Not Applicable. Requested assertion rule: only an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification could support PP5.
The ClinGen Hearing Loss VCEP v2.0 specification explicitly marks BP1 as 'Not Applicable' for the genes in this specification set (including GJB2). The panel's governing framework is used here in place of generic ACMG/AMP guidance per curation priority rules.
ClinGen Hearing Loss VCEP v2.0: BP1 Not Applicable for GJB2.
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_004004.6:c.445G>A in GJB2 is a missense substitution predicted to produce NP_003995.2:p.(Ala149Thr). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_repeat_region_indel
BP5 is not applicable. The GJB2 disease context in the Hearing Loss VCEP framework is autosomal recessive, and the VCEP explicitly states that BP5 must not be used for autosomal-recessive disease because an individual may be a carrier of a pathogenic variant while having an alternate cause.
Hearing Loss VCEP v2.0 BP5: autosomal recessive—do not use.
BP6 is not applicable under the Hearing Loss VCEP specification. Independently, no exact-variant ClinVar benign or likely benign expert-panel classification is present; ordinary laboratory submissions and aggregate ClinVar labels cannot trigger BP6.
Hearing Loss VCEP v2.0: BP6 Not Applicable. Requested assertion rule: only an exact-variant ClinVar expert-panel Benign/Likely benign classification could support BP6.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004004.6:c.445G>A in GJB2 is a missense substitution predicted to produce NP_003995.2:p.(Ala149Thr). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
Every interpreted variant in GJB2, mapped onto the exon structure of NM_004004.6. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Middle Eastern2 / 6,084 | 0.00033 |
| European (non-Finnish)77 / 1,180,048 | 6.5e-05 |
| Remaining individuals2 / 62,486 | 3.2e-05 |
| East Asian1 / 44,890 | 2.2e-05 |
| European (Finnish)1 / 63,934 | 1.6e-05 |
| South Asian1 / 91,086 | 1.1e-05 |
| Remaining individuals1 / 7,226 | 0.00014 |
| European (non-Finnish)13 / 128,832 | 0.0001 |
| African/African American1 / 24,926 | 4e-05 |
| South Asian1 / 30,614 | 3.3e-05 |
This variant is present in gnomAD v4.1 (AF= 5.20453e-05; MAF= 0.00520%, 84/1613980 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000328731; MAF= 0.03287%, 2/6084 alleles, homozygotes = 0); grpmax FAF= 5.798e-05.
This variant is present in gnomAD v2.1 (AF= 5.66552e-05; MAF= 0.00567%, 16/282410 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138389; MAF= 0.01384%, 1/7226 alleles, homozygotes = 0); grpmax FAF= 6.029e-05.
Absent from gnomAD-Canada v1.0.
The GJB2 VCEP BP4 rule (cspec v2.0) awards BP4_Supporting when 'REVEL score <=0.15 or no impact to splicing in MaxEntScan.' REVEL for this variant is 0.499, which does not meet the <=0.15 BP4 threshold (nor the >=0.7 PP3 threshold), so the missense-score sub-path is neutral/uninformative. The splice sub-path was assessed with the pipeline's available splice predictor, SpliceAI Lookup (max delta score = 0.00; no native site disruption, no cryptic site creation predicted), satisfying the 'no impact to splicing' clause of the VCEP's BP4 rule even though the VCEP names MaxEntScan specifically and no MaxEntScan output exists in this case. Given the SpliceAI result is unambiguous (delta = 0.00 across donor/acceptor gain/loss proxies) and c.445G>A lies deep within the coding exon with no proximity to splice consensus sequences, BP4_Supporting is applied on the splicing sub-path. Flagged for human review because the VCEP's named tool (MaxEntScan) was not available and SpliceAI was substituted.
cspec_v2.0_GJB2_BP4
GJB2 is governed by the ClinGen Hearing Loss VCEP (cspec v2.0), which specifies for PP3: award if REVEL score >=0.7, OR if splicing is predicted to be impacted (creation of a cryptic splice site or disruption of a native splice site). NM_004004.6:c.445G>A (p.Ala149Thr) is a missense substitution deep within the single coding exon (exon 2) of GJB2, not a splice-region variant. Local REVEL lookup gives a score of 0.499 (prefetch.json/source_registry.json), well below the VCEP's 0.7 PP3 threshold, so the missense sub-path does not support PP3. The splice sub-path was assessed using the pipeline's SpliceAI Lookup screen (source_registry key 'spliceai'; evidence.json) rather than MaxEntScan (no MaxEntScan output is present in this case bundle), which returned a maximum delta score of 0.00 -- no predicted disruption of a native site and no predicted cryptic splice site creation. Neither sub-path supports a deleterious computational prediction, so PP3 is not met.
cspec_v2.0_GJB2_PP3
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004004.6:c.445G>A in GJB2 is a missense substitution predicted to produce NP_003995.2:p.(Ala149Thr). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false; framework_mode=unstructured_ruleset); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.499. BayesDel score = 0.0972862.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Thirteen different missense mutations were identified, five of which corresponded to previously unreported changes (G12V, S19T, L90P, A149T, and P173R; Table 1). ... An amino acid change, A149T, was detected in a congenital case in which the second GJB2 mutated allele was not identified. ... So far, mutations F83L, R127H, and A149T are not clearly deafness mutations. Functional studies, such as those performed for M34T (White et al. 1998) and R75W (Richard et al. 1998b), will be required for these missense changes.
Results, paragraphs 4 and 5; Table 1; Discussion, final paragraph on missense mutations
Mutation c.101T>C (M34T) was found in compound heterozygosity with c.446G>A (A149T) in a patient with profound HI and familial background (1 of 102 cases). Mutation A149T was originally reported by Rabionet and coworkers in 2000 (Rabionet et al., 2000). Due to the lack of a second mutation in the patient analyzed in this study, the disease relevance of this DNA variant was not substantiated.
Results and Discussion, paragraph beginning ‘Mutation c.101T>C (M34T)’; Table 1
p.M34T, which occurred with no additional mutation or with p.A147T [c.445G > A]
Results, ‘Mutations’ subsection, paragraph describing patient genotypes
A149T/wt 445G[A 1 Profound [12] ... The V153I was found in one patient in homozygous and in four patients in heterozygous form which one of them had compound heterozygous V153I/A149T. ... The other mutations (M34V, N169T, A149T, and L28I) and V198M had an allele frequency of 1 and 2 % respectively. ... Rabionet et al. reported A149T variant, a missense mutation with nucleotide change of G to A at 445, which is located in transmembrane domains and not clearly a deafness mutation [12].
Results, paragraph 2; Table 1; Results, paragraph 4; Discussion, paragraph 5
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This variant is present in gnomAD v4.1 (AF= 5.20453e-05; MAF= 0.00520%, 84/1613980 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000328731; MAF= 0.03287%, 2/6084 alleles, homozygotes = 0); grpmax FAF= 5.798e-05.
This variant is present in gnomAD v2.1 (AF= 5.66552e-05; MAF= 0.00567%, 16/282410 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138389; MAF= 0.01384%, 1/7226 alleles, homozygotes = 0); grpmax FAF= 6.029e-05.
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 44751)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.499. BayesDel score = 0.0972862.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.