rs201864483

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6

The NM_000492.4(CFTR):c.2684G>A(p.Ser895Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000731 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:4

Conservation

PhyloP100: 0.459

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a domain ABC transmembrane type-1 2 (size 296) in uniprot entity CFTR_HUMAN there are 53 pathogenic changes around while only 8 benign (87%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008795202).

BP6

Variant 7-117603558-G-A is Benign according to our data. Variant chr7-117603558-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53543.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=8, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2684G>A	p.Ser895Asn	missense_variant	17/27	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.2684G>A	p.Ser895Asn	missense_variant	17/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152210

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:

0.00269

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:

0.000350

AC:

AN:

251266

Hom.:

AF XY:

0.000361

AC XY:

AN XY:

135794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00478

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:

0.0000712

AC:

104

AN:

1461632

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00239

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000740

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 22, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

CFTR-related disorder

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 30, 2023	The CFTR c.2684G>A variant is predicted to result in the amino acid substitution p.Ser895Asn. This variant has been reported in patients with pancreatitis (Table 3, Palermo et al. 2016. PubMed ID: 27171515; Chang et al. 2007. PubMed ID: 17539902; Chang et al. 2015. PubMed ID: 25869325) and bronchiectasis (Guan et al. 2018. PubMed ID: 29997923). The patient discussed in Guan et al. was also homozygous for a different variant in CFTR. This variant is reported in 0.46% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117243612-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 09, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2024	Observed in individuals with cystic fibrosis, bronchiectasis, congenital absence of the vas deferens, or pancreatitis, with and without additional CFTR variants reported, but familial segregation information and additional clinical information was not included (PMID: 12874665, 29997923, 34673937, 30811104, 32777524, 27171515, 28502372); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27143075, 26199320, 34276759, 27171515, 25869325, 29997923, 32777524, 32508047, 15905293, 34673937, 30811104, 28608624, 28502372, 31423445, 30558651, 30379828, 27717243, 29216686, 25580864, 17539902, 35313924, 34842611, 37313453, 27081564, 12874665, 36437957, 35858753, 10925568) -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 20, 2022	Variant summary: CFTR c.2684G>A (p.Ser895Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251266 control chromosomes, predominantly at a frequency of 0.0048 within the East Asian subpopulation in the gnomAD database. The variant occurs with an even higher frequency in the Other East-Asian (presumably mostly Chinese) sub population (i.e. with a frequency of 0.006), and although this frequency is not higher than the estimated maximum expected for a pathogenic variant in CFTR causing Cystic Fibrosis (CF) in the Caucasian population (0.013), however, in a recent study the estimated Chinese CF prevalence was reported to be about 40x lower than the prevalence in Caucasians (Ni_2022), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.2684G>A, has been reported in the literature in four Chinese individuals affected with Cystic Fibrosis (Wu_2000, Alper_2003, Wang_2019, Yang_2021), however, in all of these patients the variant occurred in cis with a pathogenic variant (c.2083dupG (p.Glu695fs)), and all patients also carried a pathogenic variant (c.1898+5G>T) in trans, therefore these co-occurrences with other pathogenic variants provide supporting evidence for a benign role. The variant was also reported in two Chinese patients affected with congenital absence of vas deferens (CAVD; Luo_2021), however one of these patients also carried the variant c.2083dupG (p.Glu695fs) which was described earlier in cis in four Chinese CF patients, while the other patient carried two (potentially) pathogenic variants which could explain the phenotype (though the phase was not specified). In addition, the variant was published in heterozygous state in individuals affected with pancreatitis (Chang_2015, Palermo_2016) and bronchiectasis (Guan_2018), but was also found in healthy subject with a similar frequency (Guan_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=5) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

May 24, 2021

- -

Breast neoplasm

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ACT Genomics,

Nov 06, 2020

The allele frequency of this variant c.2684G>A (p.Ser895Asn) is 0.0026 in East Asian of gnomAD and 0.003 in East Asian in 1000 Genomes. The variant is predicted to be tolerated by both SIFT or PolyPhen2. For these reasons, this variant has been classified as Likely Benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

2.9

DANN

Benign

0.61

DEOGEN2

Uncertain

0.45

T;.;.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.63

T;T;T;T;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.0088

T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.21

N;.;.;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

0.21

N;.;.;N;.

REVEL

Uncertain

0.35

Sift

Benign

0.58

T;.;.;T;.

Sift4G

Benign

0.16

T;.;.;T;.

Polyphen

0.0

B;.;.;.;.

Vest4

0.11

MVP

0.90

MPC

0.0042

ClinPred

0.010

GERP RS

1.6

Varity_R

0.031

gMVP

0.57

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