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.COL4A2 encodes a subunit of type IV collagen, a key structural component of basement membranes that support blood vessels and other tissues. Mutations in this gene are associated with cerebral small vessel disease, porencephaly, and related vascular-brain disorders. The protein's C-terminal fragment, canstatin, inhibits angiogenesis and tumor growth, giving the gene a role in suppressing cancer progression.
The recorded framework is Not recorded. 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.
Met: nonsense variant truncates the protein at residue 1395 of ~1712, removing the essential triple-helix and NC1 domains, consistent with loss of function.
Met at supporting: only one gnomAD v4.1 allele and absence from gnomAD v2.1 and gnomAD-Canada.
Met at supporting: SpliceAI predicts no splice impact (max delta 0.019), well below the 0.2 high-recall cutoff.
Generic ACMG/AMP fallback: PVS1 (very strong) plus PM2 and BP4 (supporting) give conflicting evidence, resulting in a VUS classification.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1 / 1,613,616 alleles. Recorded AF 6.19726e-07. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.019. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Likely pathogenic. ClinVar API review status: criteria provided, single submitter.
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 Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 7 not met · 10 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 applied at very strong strength for the p.(Gln1395Ter) nonsense variant based on the generic ClinGen SVI PVS1 framework (no gene-specific COL4A2 VCEP/CSPEC PVS1 rules were found in this case bundle), supported by the case's own gene-level LoF eligibility gate and variant-level nonsense classification, with the caveat that exact exon-level NMD boundary data was not directly computed.
COL4A2 has no ClinGen VCEP CSPEC in this case (framework_mode=generic_acmg, cspec.found=false), so generic ACMG/AMP PS3/BS3 definitions were applied as the fallback standard.
A targeted search of the consolidated criteria_evidence_bundle.txt (covering review_manifest, case_summary, source_registry, prefetch, evidence, literature_pass, vcep_materials, fulltext_map) for functional/assay/splicing/minigene evidence returned no matches for this variant.
No PS3 or BS3 evidence is asserted; both criteria are not_assessed pending identification of a validated functional study specific to NM_001846.4:c.4183C>T.
Variant NM_001846.4:c.4183C>T / NP_001837.2:p.(Gln1395Ter) is a nonsense (stop-gain) substitution, not a missense or synonymous variant, so BayesDel/REVEL/aGVGD missense in-silico evidence for PP3/BP4 does not apply, and BP7 (synonymous) is not applicable to this variant type.
No governing VCEP-specific PP3/BP4 lookup spreadsheet was found for COL4A2 (framework_mode = generic_acmg, no cspec present), so generic calibrated computational-evidence rules were applied.
SpliceAI predicts no splice-altering effect (max delta = 0.019), which is far below the tool's own high-recall threshold (0.2, Jaganathan et al. 2019 Cell, PMID 30661751), supporting BP4 at supporting strength via the splice-impact path.
PP3 is not met: no positive calibrated computational evidence of damage is available (SpliceAI is low/benign-consistent; REVEL unavailable; BayesDel lacks a verified published ACMG threshold for this pipeline).
No criteria match.
NM_001846.4:c.4183C>T predicts NP_001837.2:p.(Gln1395Ter), a nonsense variant. No official CSPEC/VCEP PVS1 framework exists for COL4A2 in this bundle, so the generic ClinGen SVI PVS1 decision tree (PMC6185798) applies via the case's own generic PVS1 fallback assessment. Gene-level PVS1 eligibility is supported: literature review confirms a germline loss-of-function disease mechanism for COL4A2 (biallelic truncating/splicing LoF variants reported as disease-causing and classified PVS1/PP5 in a compound-heterozygous case), and the pipeline's own gene-gate assessment marked PVS1 as 'eligible' with 'lof_mechanism_supported: true'. At the variant level, Q1395Ter truncates the protein at residue 1395 of a ~1712-residue protein, removing roughly 317 C-terminal residues (~18-19% of the protein), well upstream of the C-terminal NC1 domain (reported to span exons 47-48) and situated within the long collagenous triple-helix domain (reported to span exons 11-46) that is critical for heterotrimer formation and basement-membrane integrity. This magnitude and location of truncation is consistent with either nonsense-mediated decay of the transcript or, if translated, production of a severely truncated/non-functional protein lacking the essential triple-helix and NC1 trimerization domains, supporting PVS1 at very strong strength. Applying at full strength rather than a reduced strength because the truncation is distant from the final exon/terminus and falls in a domain broadly required for protein function, per the case's own suggested_default_strength of 'PVS1'.
The variant is ultra-rare across available population datasets (one gnomAD v4.1 allele; absent from gnomAD v2.1 and gnomAD-Canada), satisfying generic PM2 at supporting strength.
Generic ACMG/AMP PM2 (supporting): absent or sufficiently rare in population databases; applied at supporting strength for AF below 0.1% in the absence of a gene-specific specification.
SpliceAI predicts no significant splice impact for NM_001846.4:c.4183C>T (max delta score = 0.019 across DS_AG/DS_AL/DS_DG/DS_DL), well below the SpliceAI publication's own high-recall cutoff of 0.2 (Jaganathan et al., Cell 2019, PMID 30661751, which defines 0.2/0.5/0.8 as high-recall/recommended/high-precision thresholds for a splice-altering prediction). This supports BP4 at supporting strength via the splice-impact computational path. The missense in-silico path (REVEL/BayesDel/aGVGD) is not applicable because this variant is a nonsense (stop-gain) substitution, not a missense change, and no verified BayesDel publication/threshold is available regardless. No gene-specific VCEP PP3/BP4 lookup spreadsheet was available for COL4A2 to override this generic determination.
generic_acmg
PS2 is not met: the only case-level inheritance field reports paternal origin, not a confirmed de novo occurrence. The record does not provide the parental test report, parentage confirmation, proband phenotype, or mosaicism assessment needed to independently audit the inheritance call.
Generic ACMG/AMP fallback: PS2 requires a de novo variant in an affected individual with confirmed parental relationships; a reported paternal origin is incompatible with PS2.
PM6 is not met: PM6 is for an assumed de novo occurrence when parental confirmation is unavailable, whereas the only case-level inheritance field reports paternal origin. Underlying parental genotypes and testing documentation are absent, so this reported origin should be manually audited rather than upgraded to de novo evidence.
Generic ACMG/AMP fallback: PM6 applies only to an assumed de novo occurrence without parental confirmation; a reported paternal origin does not satisfy that premise.
NM_001846.4:c.4183C>T produces NP_001837.2:p.(Gln1395Ter), a nonsense/stop-gain substitution, not a missense or synonymous change, so the missense in-silico path (BayesDel/REVEL/aGVGD) is not applicable to this criterion for this variant. No gene-specific PP3/BP4 lookup spreadsheet from a governing VCEP was found (no cspec/VCEP materials present for COL4A2; framework_mode = generic_acmg). REVEL score is not available (found=false). BayesDel returns a local score (0.66) but per this pipeline's calibration policy no verified published PMID/threshold is available for BayesDel, so it must be treated as not_available/insufficiently calibrated rather than used to support PP3. The SpliceAI computational splicing prediction for this variant is low (max delta score = 0.019), which does not support a damaging splicing effect and therefore provides no basis to apply PP3.
generic_acmg
The exact-variant ClinVar record has a Likely pathogenic assertion from one clinical laboratory, not an expert panel. It is therefore ineligible for PP5 under the required expert-panel-only rule.
Apply PP5 only to an exact-variant ClinVar Pathogenic/Likely pathogenic expert-panel classification; ordinary laboratory submissions and aggregate labels do not qualify.
The observed allele frequency is far below any stand-alone benign population-frequency range; BA1 is not met.
Generic ACMG/AMP BA1: a frequency clearly incompatible with the relevant disorder is stand-alone benign evidence; this variant's observed frequency is not in that range.
The maximum observed population AF (8.476961314539345e-07 in non-Finnish Europeans) is far below a generic BS1 frequency threshold and is not greater than expected for COL4A2-related dominant brain small vessel disease.
Generic ACMG/AMP BS1: apply only when allele frequency is greater than expected for the disorder; the observed frequency does not satisfy this requirement.
No exact-variant ClinVar Benign/Likely benign expert-panel assertion is present. The sole exact-variant ClinVar submission is Likely pathogenic from a non-expert clinical laboratory and cannot trigger BP6.
Apply BP6 only to an exact-variant ClinVar Benign/Likely benign expert-panel classification; ordinary laboratory submissions and aggregate labels do not qualify.
No functional/biochemical assay data (e.g., collagen IV secretion, trimer assembly, minigene/splicing reporter, animal or cell-based studies) for NM_001846.4:c.4183C>T (p.Gln1395Ter) were found anywhere in the case bundle, literature pass, or VCEP materials. COL4A2 has no ClinGen CSPEC in this case (cspec.found=false; framework_mode=generic_acmg), so no VCEP-specific PS3 calibration exists to apply either. No published functional study of this specific nonsense variant was identified.
No case-control or other statistically valid enrichment data for NM_001846.4:c.4183C>T were identified. The exact-variant ClinVar record is a single laboratory submission and is not case-control evidence.
Generic ACMG/AMP PS4 requires a statistically increased prevalence of the variant in affected individuals compared with controls.
Not assessed. No affected-proband observation of NM_001846.4:c.4183C>T in trans with a pathogenic or likely pathogenic COL4A2 variant was provided. The available ClinVar record reports only paternal origin for the submitted variant and provides no second-variant or phase information.
Generic ACMG/AMP 2015 PM3: for a recessive disorder, the variant must be detected in trans with a pathogenic variant.
PP1 cannot be assessed because no informative relatives, phenotypes, genotypes, pedigree, or meioses are supplied. The reported paternal origin alone is not cosegregation evidence.
Generic ACMG/AMP fallback: PP1 requires cosegregation of the variant with disease in multiple affected family members; no cosegregation data are available.
No phenotype for the tested individual is provided. The condition label attached to the ClinVar record does not document the individual's phenotype or establish that it is highly specific for a COL4A2-related disorder.
Generic ACMG/AMP PP4 requires a patient phenotype or family history that is highly specific for a disease with a single genetic etiology.
BS2 is not assessable: the population data identify no homozygotes and provide no confirmed unaffected, age-appropriate individuals for this variably expressive dominant disorder.
Generic ACMG/AMP BS2: requires observation in a healthy adult individual for a disorder expected to be fully penetrant early in life; this requirement is not established here.
No functional/biochemical assay data showing normal/wild-type function for NM_001846.4:c.4183C>T (p.Gln1395Ter) were found in the case bundle, literature pass, or VCEP materials. As with PS3, no COL4A2 ClinGen CSPEC is available to define BS3 assay calibration, and no functional study of this specific variant was identified.
BS4 cannot be assessed. A paternal origin does not establish whether the father or other genotype-positive relatives are clinically unaffected, nor does it establish clinically meaningful non-segregation in the family.
Generic ACMG/AMP fallback: BS4 requires lack of segregation in affected family members; inheritance from a parent without that parent's phenotype and family segregation data is insufficient.
Not assessed. There is no documented observation of NM_001846.4:c.4183C>T in cis with a pathogenic variant, nor in trans with a pathogenic variant in an individual with a fully penetrant dominant disorder. Paternal origin alone does not establish either co-occurrence configuration.
Generic ACMG/AMP 2015 BP2: observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern.
No individual-level phenotype, molecular diagnosis, or evidence for an alternative molecular cause is provided; BP5 cannot be assessed.
Generic ACMG/AMP BP5 requires a variant observed in a case with an alternate molecular basis for disease.
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_001846.4:c.4183C>T in COL4A2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001837.2:p.(Gln1395Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_001846.4:c.4183C>T in COL4A2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001837.2:p.(Gln1395Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_missense
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_001846.4:c.4183C>T in COL4A2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001837.2:p.(Gln1395Ter). 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); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_001846.4:c.4183C>T in COL4A2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001837.2:p.(Gln1395Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_001846.4:c.4183C>T in COL4A2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001837.2:p.(Gln1395Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_missense
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_001846.4:c.4183C>T in COL4A2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001837.2:p.(Gln1395Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_missense
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001846.4:c.4183C>T in COL4A2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001837.2:p.(Gln1395Ter). 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); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_repeat_region_indel
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_001846.4:c.4183C>T in COL4A2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001837.2:p.(Gln1395Ter). 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); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
Every interpreted variant in COL4A2, mapped onto the exon structure of NM_001846.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)1 / 1,179,668 | 8.5e-07 |
This variant is present in gnomAD v4.1 (AF= 6.19726e-07; MAF= 0.00006%, 1/1613616 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47696e-07; MAF= 0.00008%, 1/1179668 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
SpliceAI predicts no significant splice impact for NM_001846.4:c.4183C>T (max delta score = 0.019 across DS_AG/DS_AL/DS_DG/DS_DL), well below the SpliceAI publication's own high-recall cutoff of 0.2 (Jaganathan et al., Cell 2019, PMID 30661751, which defines 0.2/0.5/0.8 as high-recall/recommended/high-precision thresholds for a splice-altering prediction). This supports BP4 at supporting strength via the splice-impact computational path. The missense in-silico path (REVEL/BayesDel/aGVGD) is not applicable because this variant is a nonsense (stop-gain) substitution, not a missense change, and no verified BayesDel publication/threshold is available regardless. No gene-specific VCEP PP3/BP4 lookup spreadsheet was available for COL4A2 to override this generic determination.
generic_acmg
NM_001846.4:c.4183C>T produces NP_001837.2:p.(Gln1395Ter), a nonsense/stop-gain substitution, not a missense or synonymous change, so the missense in-silico path (BayesDel/REVEL/aGVGD) is not applicable to this criterion for this variant. No gene-specific PP3/BP4 lookup spreadsheet from a governing VCEP was found (no cspec/VCEP materials present for COL4A2; framework_mode = generic_acmg). REVEL score is not available (found=false). BayesDel returns a local score (0.66) but per this pipeline's calibration policy no verified published PMID/threshold is available for BayesDel, so it must be treated as not_available/insufficiently calibrated rather than used to support PP3. The SpliceAI computational splicing prediction for this variant is low (max delta score = 0.019), which does not support a damaging splicing effect and therefore provides no basis to apply PP3.
generic_acmg
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_001846.4:c.4183C>T in COL4A2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_001837.2:p.(Gln1395Ter). 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); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.66.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
PM3 For recessive disorders, detected in trans with a pathogenic variant BP2 Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern
Table 5, criteria for pathogenic and benign variants
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 6.19726e-07; MAF= 0.00006%, 1/1613616 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47696e-07; MAF= 0.00008%, 1/1179668 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory). (ClinVarID = 1713186)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.66.
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.