7-117536665-C-G

Position:

chr7-117536665-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM2PM5BP4_Strong

The ENST00000003084.11(CFTR):c.861C>G(p.Asn287Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,610,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N287Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CFTR
ENST00000003084.11 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11O:1

Conservation

PhyloP100: 2.45

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 177 pathogenic changes around while only 18 benign (91%) in ENST00000003084.11

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117536663-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54069.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=6, not_provided=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.033035964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.861C>G	p.Asn287Lys	missense_variant	7/27	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.861C>G	p.Asn287Lys	missense_variant	7/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152188

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:

0.00173

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:

0.000109

AC:

AN:

248836

Hom.:

AF XY:

0.0000817

AC XY:

AN XY:

134668

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00147

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:

0.0000295

AC:

AN:

1458614

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

725734

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000860

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:5Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 23, 2022	CFTR c.861C>G has been identified as a single heterozygous variant in multiple individuals with congenital bilateral absence of the vas deferens and has been reported in ClinVar (Variation ID: 54071). This variant (rs112162204) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the East Asian subpopulation (gnomAD: 33/19904 alleles; 0.1658%, no homozygotes). Three bioinformatic tools queried predict that this substitution would be tolerated, while the asparagine residue at this position is evolutionarily conserved across many of the species assessed. We consider the clinical significance of CFTR c.861C>G to be uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 14, 2022	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 287 of the CFTR protein (p.Asn287Lys). This variant is present in population databases (rs112162204, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 54071). 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 not expected to disrupt CFTR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2023	The p.N287K variant (also known as c.861C>G), located in coding exon 7 of the CFTR gene, results from a C to G substitution at nucleotide position 861. The asparagine at codon 287 is replaced by lysine, an amino acid with similar properties. This variant was identified in a Taiwanese man with congenital bilateral absence of the vas deferens; a second CFTR alteration was not detected (Wu CC et al. Hum. Reprod., 2005 Sep;20:2470-5). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 28, 2022	The frequency of this variant in the general population, 0.0017 (33/19904 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with cystic fibrosis (CF) (PMID: 26708955 (2016)), congenital bilateral absence of the vas deferens (CBAVD) (PMID: 15905293 (2005) 32777524, (2021)), enteric fever (PMID: 20233062 (2010)), and intrahepatic cholestasis (PMID: 31450232 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with congenital bilateral absence of the vas deferens (CBAVD) without a second CFTR variant identified and in patients with CAVD, cystic fibrosis, or intrahepatic cholestasis with no information provided on whether other CFTR variants were also identified (Wu et al., 2005; Schrijver et al., 2016; Wang et al., 2020; Luo et al., 2021); This variant is associated with the following publications: (PMID: 35913788, 15905293, 32777524, 26708955, 26471113, 29216686, 20233062, 35313924, 31450232) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 02, 2024

Variant summary: CFTR c.861C>G (p.Asn287Lys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 248836 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk (0.00011 vs 0.0063), allowing no conclusion about variant significance. c.861C>G has been reported in the literature in individuals affected with CBAVD, cystic fibrosis, enteric fever and intrahepatic cholestasis (e.g. Wu_2005, van de Vosse_2010, Schrijver_2016, Wang_2020, Luo_2021). These reports do not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32777524, 26708955, 31450232, 15905293, 20233062). ClinVar contains an entry for this variant (Variation ID: 54071). Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 16, 2017

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

D;.;.;D;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.043

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.74

T;T;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.033

T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.93

L;.;.;.;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

N;.;.;N;.

REVEL

Uncertain

0.32

Sift

Benign

0.086

T;.;.;T;.

Sift4G

Uncertain

0.0020

D;.;.;D;.

Polyphen

0.17

B;.;.;.;.

Vest4

0.82

MutPred

0.46

Gain of ubiquitination at N287 (P = 0.0276);Gain of ubiquitination at N287 (P = 0.0276);Gain of ubiquitination at N287 (P = 0.0276);.;Gain of ubiquitination at N287 (P = 0.0276);

MVP

0.97

MPC

0.0039

ClinPred

0.11

GERP RS

3.2

Varity_R

0.29

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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