7-117666961-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_000492.4(CFTR):c.4296C>G(p.Asn1432Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,908 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 Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: -1.25

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 0 ACMG points.

PM1

In a domain ABC transporter 2 (size 233) in uniprot entity CFTR_HUMAN there are 28 pathogenic changes around while only 3 benign (90%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06646529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.4296C>G	p.Asn1432Lys	missense_variant	Exon 27 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.4296C>G	p.Asn1432Lys	missense_variant	Exon 27 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250878

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135594

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:3

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1432 of the CFTR protein (p.Asn1432Lys). This variant is present in population databases (rs761669740, gnomAD 0.003%). 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: 824764). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. 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. -

Sep 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N1432K variant (also known as c.4296C>G), located in coding exon 27 of the CFTR gene, results from a C to G substitution at nucleotide position 4296. The asparagine at codon 1432 is replaced by lysine, an amino acid with similar properties. This variant has been identified in a heterozygous control individual (Schneider A et al. Gastroenterology, 2011 Jan;140:162-71). This amino acid position is poorly 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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder

Uncertain:2

Sep 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.4296C>G variant is predicted to result in the amino acid substitution p.Asn1432Lys. This variant has been reported in a control individual from a chronic pancreatitis cohort study (Table 1, Schneider et al. 2011. PubMed ID: 20977904). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117307015-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Sep 18, 2018

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Uncertain:1

May 20, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.23

DANN

Benign

0.94

DEOGEN2

Benign

0.36

T;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.066

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.91

L;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.63

N;N;.

REVEL

Benign

0.27

Sift

Benign

0.36

T;T;.

Sift4G

Uncertain

0.0040

D;D;.

Polyphen

0.062

B;.;.

Vest4

0.18

MutPred

0.32

Gain of methylation at N1432 (P = 0.0126);.;.;

MVP

0.64

MPC

0.0039

ClinPred

0.075

GERP RS

-7.7

Varity_R

0.23

gMVP

0.41

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