rs397508463

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000492.4(CFTR):c.2939T>A(p.Ile980Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000113 in 1,593,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2O:1

Conservation

PhyloP100: 4.46

Variant links:

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 50) in uniprot entity CFTR_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 7-117606704-T-A is Pathogenic according to our data. Variant chr7-117606704-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53604.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, not_provided=1, Uncertain_significance=2, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2939T>A	p.Ile980Lys	missense_variant	18/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2939T>A	p.Ile980Lys	missense_variant	18/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.178-1715A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251150

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000971

AC:

AN:

1441576

Hom.:

Cov.:

AF XY:

0.00000835

AC XY:

AN XY:

718722

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:2Uncertain:1Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 14, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 27, 2023	The p.I980K variant (also known as c.2939T>A), located in coding exon 18 of the CFTR gene, results from a T to A substitution at nucleotide position 2939. The isoleucine at codon 980 is replaced by lysine, an amino acid with dissimilar properties. This variant was reported in two individuals, who also had another pathogenic mutation, with congenital bilateral absence of the vas deferens (CBAVD). One individual also had an elevated sweat chloride concentration and presented with chronic sinusitis, nasal polyposis and pancreatic sufficiency (Bienvenu et al. Hum Mutat. 1996;7:182). In another study, this variant was seen in two patients in a cohort of 305 with CBAVD, of which one individual also had p.R117H and the other individual had c.3605delA, however further clinical information was not provided (Steiner et al. Hum Mutat. 2011;32:912-20). In a group of 110 patients who were diagnosed with cystic fibrosis by two abnormal sweat chloride levels and/or two CFTR mutations, one was reported with this variant (Hubert et al. Eur. Respir. J. 1996;9(11):2207-14). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 10, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 980 of the CFTR protein (p.Ile980Lys). This variant is present in population databases (rs397508463, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital absence of the vas deferens and/or cystic fibrosis (PMID: 8829643, 8947061, 11101688, 21520337). ClinVar contains an entry for this variant (Variation ID: 53604). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 19, 2021

- -

CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 02, 2024

Variant summary: CFTR c.2939T>A (p.Ile980Lys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-06 in 251838 control chromosomes. c.2939T>A has been reported in the literature in the presumed compound heterozygous or compound heterozygous state in multiple individuals affected with clinical features of Congenital Bilateral Absence Of The Vas Deferens and/or Cystic Fibrosis and/or CFTR-related disorders (example, Bienvenu_1997, Claustres_2000, Hubert_1996, Jezequel_2000, Steiner_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 13.43% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 8829643, 10923036, 20059485, 9272157, 8947061, 11101688, 21520337, 38388235). ClinVar contains an entry for this variant (Variation ID: 53604). Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 17, 2019

The CFTR c.2939T>A; p.Ile980Lys variant (rs397508463) is reported in the literature in multiple individuals affected with congenital absence of the vas deferens (CBAVD) or cystic fibrosis (CF) (Bienvenu 1996, Hubert 1996, Jezequel 2000, Steiner 2011). In all affected individuals carrying this variant, a second pathogenic variant was also identified (Bienvenu 1996, Hubert 1996, Jezequel 2000, Steiner 2011). The p.Ile980Lys variant is present on only two chromosomes (2/251150 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The isoleucine at codon 980 is moderately conserved, but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Despite its prevalence in affected individuals, due to limited information, the significance of the p.Ile980Lys variant is uncertain at this time. References: Bienvenu T et al. A novel missense mutation in exon 16 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene identified in CBAVD patients. Hum Mutat. 1996;7(2):182. Hubert D et al. Genotype-phenotype relationships in a cohort of adult cystic fibrosis patients. Eur Respir J. 1996 Nov;9(11):2207-14. Jezequel P et al. Molecular screening of the CFTR gene in men with anomalies of the vas deferens: identification of three novel mutations. Mol Hum Reprod. 2000 Dec;6(12):1063-7. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.91

D;.;.;D;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D;D;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Pathogenic

3.4

M;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-4.0

D;.;.;D;.

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

D;.;.;D;.

Sift4G

Uncertain

0.0040

D;.;.;D;.

Polyphen

0.048

B;.;.;.;.

Vest4

0.93

MutPred

0.95

Gain of ubiquitination at I980 (P = 0.023);.;.;.;.;

MVP

0.98

MPC

0.0053

ClinPred

0.97

GERP RS

5.4

Varity_R

0.95

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over