rs397508332

Positions:

chr7-117509071-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS2_Supporting

The NM_000492.4(CFTR):c.202A>G(p.Lys68Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000899 in 1,612,996 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 2 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1O:1

Conservation

PhyloP100: 5.45

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:

CFTR (HGNC:):

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 76) in uniprot entity CFTR_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000492.4

BP4

Computational evidence support a benign effect (MetaRNN=0.1906983).

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.202A>G	p.Lys68Glu	missense_variant	3/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.202A>G	p.Lys68Glu	missense_variant	3/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152224

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:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000159

AC:

AN:

251006

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135664

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:

0.000784

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000917

AC:

134

AN:

1460654

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

726724

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:

0.000916

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:3Benign:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 08, 2018	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2023	The p.K68E variant (also known as c.202A>G), located in coding exon 3 of the CFTR gene, results from an A to G substitution at nucleotide position 202. The lysine at codon 68 is replaced by glutamic acid, an amino acid with similar properties. This variant was described in an individual with mild cystic fibrosis phenotype, who had a splice site variant on the other chromosome (Kilinç MO et al. Am. J. Med. Genet., 2002 Dec;113:250-7). This alteration was also identified in heterozygous state in an individual with pancreatic insufficiency and elevated sweat chloride levels (Alibakhshi R et al. J. Cyst. Fibros., 2008 Mar;7:102-9). This variant was also reported in a pancreatitis cohort (Jalaly NY et al. Am J Gastroenterol, 2017 Aug;112:1320-1329). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 09, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 21, 2018	- -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 20, 2024

The CFTR c.202A>G variant is predicted to result in the amino acid substitution p.Lys68Glu. This variant, described at nucleotide position 334 in legacy nomenclature, has been reported in the compound heterozygous state in an individual with mild cystic fibrosis (CF) who had pancreatic sufficiency and a borderline sweat chloride test (60 mEq/L) and in an individual with CF with pancreatic insufficiency and elevated sweat chloride, in whom a second CFTR variant was not found (Kilinc et al. 2002. PubMed ID: 12439892; Alibakhshi et al. 2007. PubMed ID: 17662673). This variant has also been reported in the heterozygous state in individuals with CF or CFTR-related disorders, chronic obstructive pulmonary disease, chronic pancreatitis, and congenital absence of vas deferens (Table 1, Amato et al. 2011. PubMed ID: 22020151; Table 2, Trujillano et al. 2015. PubMed ID: 26436105; Table 1, Jalaly et al. 2017. PubMed ID: 28440306; Supplementary Table 1, Saferali et al. 2022. PubMed ID: 34996830). However, this variant has also been found in the heterozygous state in a control individual from a study of patients with chronic pancreatitis and a control individual from a study of patients with congenital bilateral absence of the vas deferens (Supporting Tables S4 and S5, Steiner et al. 2011. PubMed ID: 21520337). In vitro functional studies suggest that this variant impairs CFTR function, although the protein retains 40-60% residual activity compared to control (Table 1, Baldassarri et al. 2022. PubMed ID: 36552859). This variant is reported in 0.078% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.;.;T;.

Eigen

Benign

0.092

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.19

T;T;T;T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.2

M;.;.;.;M

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.3

N;.;.;N;.

REVEL

Pathogenic

0.65

Sift

Uncertain

0.024

D;.;.;D;.

Sift4G

Uncertain

0.0030

D;.;.;D;.

Polyphen

0.25

B;.;.;.;.

Vest4

0.90

MVP

0.98

MPC

0.0041

ClinPred

0.089

GERP RS

4.5

Varity_R

0.34

gMVP

0.88

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