About CFTR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CFTR c.2723C>G, p.(Thr908Ser)
Classification
Uncertain significance
Variant description:
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.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present in gnomAD v4.1 at an extremely low allele frequency (2.48e-6; 4/1,613,954 alleles, 0 homozygotes), absent from gnomAD v2.1, and absent from gnomAD-Canada v1.0. The frequency is well below the 0.1% threshold for PM2.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
4 / 1,613,954 alleles
gnomAD v4.1: 4 / 1,613,954 alleles. Recorded AF 2.47839e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 7 not met · 14 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000492.4:c.2723C>G (p.Thr908Ser) is a missense variant in exon 17 of CFTR, a gene in which both missense and loss-of-function variants are established disease mechanisms for cystic fibrosis and CFTR-related disorders.
This variant is present in gnomAD v4.1 at an extremely low allele frequency (2.48e-6; 4/1,613,954 alleles, 0 homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada v1.0, meeting PM2 at supporting strength.
Computational evidence is conflicting: REVEL score 0.557 is borderline, BayesDel score -0.037 is neutral, and SpliceAI max delta score 0.02 predicts no splicing impact; thus PP3 is not met and BP4 is not met.
ClinVar classifies this variant as Uncertain significance based on a single clinical laboratory submission (GeneDx, SCV002549489, criteria provided, single submitter). No functional studies, segregation data, de novo observations, or case-control data were identified.
With only one supporting pathogenic criterion (PM2) and no benign criteria met, the evidence is insufficient to meet thresholds for Likely Pathogenic or Likely Benign classification. The variant is classified as Uncertain significance per ACMG/AMP 2015 guidelines.
No criteria match.
Met · 1
PM2 SupportingThis variant is present in gnomAD v4.1 at an extremely low allele frequency (2.48e-6; 4/1,613,954 alleles, 0 homozygotes), absent from gnomAD v2.1, and absent from gnomAD-Canada v1.0. The frequency is well below the 0.1% threshold for PM2. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=2.48e-6
- 4/1
- 613
- 954 alleles
- 0 homozygotes
- grpmax FAF=7.9e-7
- gnomAD v2.1: absent
- gnomAD-Canada v1.0: absent
Sources
Not met · 7 · evaluated, threshold not reached
PP3 Multiple lines of computational evidence are conflicting and do not support a deleterious effect. REVEL score 0.557 is borderline and does not strongly predict pathogenicity. BayesDel score -0.037 is in the neutral range. SpliceAI max delta score 0.02 predicts no splicing impact. The ClinVar submitter's in silico analysis also indicated the variant does not alter protein structure/function. Details ▾Hide ▴
Evidence considered
- REVEL: 0.557 (borderline
- >0.5 threshold but not strongly pathogenic)
- BayesDel: -0.037 (neutral range)
- SpliceAI max delta: 0.02 (no significant splice impact)
- ClinVar submitter (GeneDx): in silico analysis supports no alteration of protein structure/function
Sources
PP5 ClinVar classifies this variant as Uncertain significance (1 submitter, criteria provided, single submitter). No reputable source has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 1697071: Uncertain significance
- 1 submitter (GeneDx)
Sources
BA1 The maximum population allele frequency for this variant is 2.48e-6 (gnomAD v4.1), which is far below the 1% threshold for BA1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF: 2.48e-6
- gnomAD v2.1: absent
- gnomAD-Canada: absent
Sources
BS1 The maximum population allele frequency for this variant is 2.48e-6 (gnomAD v4.1), which is far below the 0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 total AF: 2.48e-6
- gnomAD v2.1: absent
- gnomAD-Canada: absent
Sources
BS2 No homozygotes have been observed in gnomAD (0/1,613,954 alleles). For CFTR, a recessive disorder, observation in a healthy homozygous adult individual would be required. This variant has not been observed in the homozygous state in any population database. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 0 homozygotes
- gnomAD v2.1: absent
- gnomAD-Canada: absent
Sources
BP4 Multiple lines of computational evidence do not agree on a lack of impact. REVEL score 0.557 exceeds the 0.5 threshold in the damaging range. While BayesDel -0.037 and SpliceAI max delta 0.02 are neutral, the evidence does not show consistent support for no effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.557 (>0.5 damaging range)
- BayesDel: -0.037 (neutral)
- SpliceAI max delta: 0.02 (no splice impact)
Sources
BP6 ClinVar classifies this variant as Uncertain significance (1 submitter). No reputable source has reported this variant as benign. Details ▾Hide ▴
Not assessed · 14 · no assessment recorded
PS1 No pathogenic variant at the same codon (Thr908) with the same amino acid change resulting from a different nucleotide substitution has been identified. Details ▾Hide ▴
Still missing
- No data on alternate nucleotide changes producing Thr908Ser
PS2 No de novo observation with confirmed maternity and paternity is available for this variant. Details ▾Hide ▴
Still missing
- No de novo data available
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect were identified for this variant. Details ▾Hide ▴
Still missing
- No functional studies identified
PS4 No case-control data demonstrating significantly increased prevalence in affected individuals versus controls is available. Details ▾Hide ▴
Still missing
- No case-control data available
PM1 The variant is not located in a statistically significant mutational hotspot. Without VCEP-specified functional domain coordinates or additional domain-level evidence, PM1 cannot be assessed. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue not significant
- variant not listed in statistically significant hotspots
Still missing
- No VCEP/CSPEC domain specification available for CFTR
- position 908 domain context not evaluated
PM6 No de novo observation (without confirmed maternity and paternity) is available for this variant. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 No co-segregation data in affected family members is available. Details ▾Hide ▴
Still missing
- No segregation data available
PP2 HCI prior is not available for CFTR; gene-specific constraint metrics cannot be evaluated. Without evidence that CFTR has a low rate of benign missense variation, PP2 cannot be assessed. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported
- no constraint data available
Still missing
- No gene-level missense constraint data available for CFTR
PP4 No patient phenotype or family history data is available to assess disease specificity. Details ▾Hide ▴
Still missing
- No phenotype data available
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect were identified for this variant. Details ▾Hide ▴
Still missing
- No functional studies identified
BS4 No segregation data in affected family members is available. Details ▾Hide ▴
Still missing
- No segregation data available
BP2 No data on this variant observed in trans with a pathogenic variant or in cis with a pathogenic variant is available. Details ▾Hide ▴
Still missing
- No trans/cis configuration data available
BP5 No data on this variant found in a case with an alternate molecular basis for disease is available. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
PS5 No data on this variant found in trans with a pathogenic CFTR variant is available. CFTR-associated disease is recessive; trans data would require identification of a second pathogenic allele. Details ▾Hide ▴
Still missing
- No trans configuration data available
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.2723C>G, p.Thr908Ser), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 framework (PMC6185798) does not apply to missense variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false per PVS1 variant assessment
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ANo data available to assess this variant in trans with a pathogenic CFTR variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis variant is a substitution, not an in-frame indel or stop-loss variant. PM4 does not apply. Details ▾Hide ▴
Evidence considered
- Variant type is substitution
PM5 N/ANo comparator missense variants at codon 908 with an established pathogenic classification were identified. PM5 candidate harvesting returned no eligible candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate collection: 0 same-residue candidates
- 0 expert panel P/LP candidates
Sources
pm5_candidates
BP1 N/ACFTR-associated disease results from both missense and loss-of-function variants. CFTR is not a gene where primarily truncating variants cause disease; BP1 does not apply. Details ▾Hide ▴
Evidence considered
- CFTR disease mechanism includes both missense and truncating variants
BP3 N/AThis variant is a substitution, not an in-frame insertion or deletion. BP3 applies only to in-frame indels. Details ▾Hide ▴
Evidence considered
- Variant type is substitution
BP7 N/AThis is a missense variant (c.2723C>G, p.Thr908Ser), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant type is missense
Identifiers
- Gene
- CFTR
- Transcript
- NM_000492.4
- Coding (HGVS c.)
- NM_000492.4:c.2723C>G
- Protein (HGVS p.)
- NP_000483.3:p.(Thr908Ser)
- GRCh38
- chr7:117603597 C>G
- GRCh37
- chr7:117243651 C>G
- ClinVar
- 1697071
Gene diagram
Every interpreted variant in CFTR, mapped onto the exon structure of NM_000492.4. Select a row to find it on the plot.
CFTRNM_000492.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CFTR
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
4 / 1,613,954 alleles
AF 2.48e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,613,954 alleles · 0 hom · FAF 7.9e-07
| European (non-Finnish)4 / 1,179,850 | 3.4e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.47839e-06; MAF= 0.00025%, 4/1613954 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.39026e-06; MAF= 0.00034%, 4/1179850 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.557
- BayesDel
- -0.037
How the predictions were used
PP3 Multiple lines of computational evidence are conflicting and do not support a deleterious effect. REVEL score 0.557 is borderline and does not strongly predict pathogenicity. BayesDel score -0.037 is in the neutral range. SpliceAI max delta score 0.02 predicts no splicing impact. The ClinVar submitter's in silico analysis also indicated the variant does not alter protein structure/function. Details ▾Hide ▴
Evidence considered
- REVEL: 0.557 (borderline
- >0.5 threshold but not strongly pathogenic)
- BayesDel: -0.037 (neutral range)
- SpliceAI max delta: 0.02 (no significant splice impact)
- ClinVar submitter (GeneDx): in silico analysis supports no alteration of protein structure/function
Sources
BP4 Multiple lines of computational evidence do not agree on a lack of impact. REVEL score 0.557 exceeds the 0.5 threshold in the damaging range. While BayesDel -0.037 and SpliceAI max delta 0.02 are neutral, the evidence does not show consistent support for no effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.557 (>0.5 damaging range)
- BayesDel: -0.037 (neutral)
- SpliceAI max delta: 0.02 (no splice impact)
Sources
BP7 N/AThis is a missense variant (c.2723C>G, p.Thr908Ser), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant type is missense
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.557. BayesDel score = -0.0370847.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
4 / 1,613,954 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1697071/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-117243651-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-117603597-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-117603597-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000492.4%3Ac.2723…
- OncoKB ↗www.oncokb.org/gene/CFTR/T908S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CFTR+c.2723C%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.47839e-06; MAF= 0.00025%, 4/1613954 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.39026e-06; MAF= 0.00034%, 4/1179850 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1697071)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.557. BayesDel score = -0.0370847.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.