rs397508462

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000492.4(CFTR):c.2936A>C(p.Asp979Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000879 in 1,591,906 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D979V) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4O:1

Conservation

PhyloP100: 8.62

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 Pathogenic. Variant got 11 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117606701-A-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 7-117606701-A-C is Pathogenic according to our data. Variant chr7-117606701-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53602.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, not_provided=1, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2936A>C	p.Asp979Ala	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.2936A>C	p.Asp979Ala	missense_variant	18/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.178-1712T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251154

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000489

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000834

AC:

AN:

1439644

Hom.:

Cov.:

AF XY:

0.00000836

AC XY:

AN XY:

717908

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000279

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.16e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:1Uncertain:2Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 979 of the CFTR protein (p.Asp979Ala). This variant is present in population databases (rs397508462, gnomAD 0.05%). This missense change has been observed in individuals with clinical features of CFTR-related conditions (PMID: 9493456, 10376575, 32020786, 34782259). ClinVar contains an entry for this variant (Variation ID: 53602). 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%. Experimental studies have shown that this missense change affects CFTR function (PMID: 11118444). This variant disrupts the p.Asp979 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9401110, 29805046). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 18, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 20, 2024	The p.D979A variant (also known as c.2936A>C), located in coding exon 18 of the CFTR gene, results from an A to C substitution at nucleotide position 2936. The aspartic acid at codon 979 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been detected in three individuals who also carried the 5T variant. All three individuals had congenital bilateral absence of vas deferens (CBAVD) and one also had recurrent infections, a sweat chloride level of 55mM, and 75% forced expiratory volume (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77; Mak V et al. JAMA, 1999 Jun;281:2217-24). In one functional study, this alteration was analyzed as part of a complex allele (p.R347H-p.D979A). Authors found that the alteration lead to misprocessing of CFTR and was critical for proper chloride channel function. In addition, they found that the complex allele combination lead to a dramatic decrease in chloride current. (Clain J et al. J. Biol. Chem., 2001 Mar;276:9045-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2020	The CFTR c.2936A>C; p.Asp979Ala variant (rs397508462) is reported in the literature in individuals affected with congenital absence of vas deferens who carry a mildly pathogenic variant in CFTR (Dork 1997, Mak 1999, Wilschanski 2006), but is also reported in individuals with pancreatitis who carry variants in other pancreatitis-associated genes (Zou 2018), and in a pair of twins with cystic fibrosis who carry two pathogenic CFTR variants on opposite chromosomes (Hojo 1997). Functional assays show that the p.Asp979Ala variant result in a mild defect (Clain 2001). The p.Asp979Ala variant is reported in the ClinVar database (Variation ID: 53602), and is found in the East Asian population with an allele frequency of 0.05% (9/18394 alleles) in the Genome Aggregation Database. The asparagine at codon 979 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. A different variant at this codon, p.Asp979Val, is reported as a CF-causing variant in the CFTR2 database (see CFTR2 database link). While the p.Asp979Ala variant is not predicted to cause classic cystic fibrosis, based on available information, the clinical significance is uncertain for CFTR-related disorders. References: CFTR2 database: https://cftr2.org/ Clain J et al. Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function. J Biol Chem. 2001 Mar 23;276(12):9045-9. Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 Sep;100(3-4):365-77. Hojo S et al. (Two cases of cystic fibrosis in Japanese/German twins). Nihon Kyobu Shikkan Gakkai Zasshi. 1997 Nov;35(11):1259-64. Mak V et al. Proportion of cystic fibrosis gene mutations not detected by routine testing in men with obstructive azoospermia. JAMA. 1999 Jun 16;281(23):2217-24. Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006 Oct 1;174(7):787-94. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15084988, 35119551, 21483833, 32777524, 30420730, 9272157, 32020786, 9493456, 34782259, 29997923, 32429104, 35858753, 26708955, 9550362, 22504961, 23820649, 9401110, 16840743, 12940920, 10376575, 20932301, 35313924, Bihler2023[Pre-print], 11118444) -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 28, 2024

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

May 07, 2024

Variant summary: CFTR c.2936A>C (p.Asp979Ala) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 253874 control chromosomes (gnomAD and publications). c.2936A>C has been reported in the literature in multiple individuals affected with Congenital Bilateral Absence Of The Vas Deferens (CBAVD) who carry the variant in trans with the pathogenic 5T allele (e.g. Dork_1997, Mak_1999, Luo_2021). In addition, the variant was found in two twin siblings with CF who carried another pathogenic mutation (p.R347H) in cis and the common disease variant p.F508del on the other allele (Hojo_1998). It was speculated that the p.D979A variant may contribute to more severe disease in these individuals, however the contributions of the individual variants to the phenotype could not be determined. The variant was also detected in several individuals with pancreatitis, however co-occurred with variants in SPINK1 and PRSS1 (e.g. Zou_2018). At least one publication reports experimental evidence evaluating an impact on protein function, suggesting that the variant results in a partial reduction of CFTR processing and moderate effects on chloride channel dynamics, consistent with the milder CFTR-related phenotype (CBAVD) that has been observed in most patients with the variant (e.g. Clain_2001). The following publications have been ascertained in the context of this evaluation (PMID: 15744523, 11118444, 9272157, 21483833, 15121783, 20932301, 9550362, 15537723, 19166122, 32777524, 10376575, 15084988, 24697796, 12940920, 16840743, 30420730, Lucarelli et al, 35858753).ClinVar contains an entry for this variant (Variation ID: 53602). Based on the evidence outlined above, the variant was classified as likely pathogenic in association with CBAVD. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;.;D;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

H;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.5

D;.;.;D;.

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.98

MutPred

0.98

Loss of ubiquitination at K978 (P = 0.1601);.;.;.;.;

MVP

1.0

MPC

0.015

ClinPred

0.99

GERP RS

5.4

Varity_R

0.99

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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