NM_000492.4:c.2723C>G

CFTR · NP_000483.3:p.(Thr908Ser) · NM_000492.4

GRCh37: chr7:117243651 C>G · GRCh38: chr7:117603597 C>G

Gene: CFTR Transcript: NM_000492.4

Final call

VUS

PM2 supporting

Variant details

Gene

CFTR

Transcript

NM_000492.4

Protein

NP_000483.3:p.(Thr908Ser)

gnomAD AF

2.478385381491666e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No pathogenic variant at the same codon (Thr908) with the same amino acid change resulting from a different nucleotide substitution has been identified.
PS2	Not assessed	No de novo observation with confirmed maternity and paternity is available for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating a damaging effect were identified for this variant.
PS4	Not assessed	No case-control data demonstrating significantly increased prevalence in affected individuals versus controls is available.
PS5	Not assessed	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.
PM1	Not assessed	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No comparator missense variants at codon 908 with an established pathogenic classification were identified. PM5 candidate harvesting returned no eligible candidates.	pm5_candidates
PM6	Not assessed	No de novo observation (without confirmed maternity and paternity) is available for this variant.
PP1	Not assessed	No co-segregation data in affected family members is available.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai clinvar
PP4	Not assessed	No patient phenotype or family history data is available to assess disease specificity.
PP5	Not met	ClinVar classifies this variant as Uncertain significance (1 submitter, criteria provided, single submitter). No reputable source has reported this variant as pathogenic.	clinvar
BA1	Not met	The maximum population allele frequency for this variant is 2.48e-6 (gnomAD v4.1), which is far below the 1% threshold for BA1.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	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.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not met	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.	gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect were identified for this variant.
BS4	Not assessed	No segregation data in affected family members is available.
BP1	N/A	CFTR-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.
BP2	Not assessed	No data on this variant observed in trans with a pathogenic variant or in cis with a pathogenic variant is available.
BP3	N/A	This variant is a substitution, not an in-frame insertion or deletion. BP3 applies only to in-frame indels.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	No data on this variant found in a case with an alternate molecular basis for disease is available.
BP6	Not met	ClinVar classifies this variant as Uncertain significance (1 submitter). No reputable source has reported this variant as benign.	clinvar
BP7	N/A	This is a missense variant (c.2723C>G, p.Thr908Ser), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
PM3	N/A	No data available to assess this variant in trans with a pathogenic CFTR variant.
PM4	N/A	This variant is a substitution, not an in-frame indel or stop-loss variant. PM4 does not apply.

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