rs17653265

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000165.5(GJA1):c.758C>T(p.Ala253Val) variant causes a missense change. The variant allele was found at a frequency of 0.0132 in 1,613,562 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0091 ( 10 hom., cov: 32)

Exomes 𝑓: 0.014 ( 199 hom. )

Consequence

GJA1
NM_000165.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.78

Variant links:

Genes affected

GJA1 (HGNC:4274): (gap junction protein alpha 1) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. The encoded protein is the major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. A related intronless pseudogene has been mapped to chromosome 5. Mutations in this gene have been associated with oculodentodigital dysplasia, autosomal recessive craniometaphyseal dysplasia and heart malformations. [provided by RefSeq, May 2014]

GJA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the GJA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.2784 (below the threshold of 3.09). Trascript score misZ: 3.3775 (above the threshold of 3.09). GenCC associations: The gene is linked to craniometaphyseal dysplasia, autosomal recessive, Hallermann-Streiff syndrome, syndactyly type 3, oculodentodigital dysplasia, nonsyndromic genetic hearing loss, hypoplastic left heart syndrome 1, autosomal dominant palmoplantar keratoderma and congenital alopecia, oculodentodigital dysplasia, autosomal recessive, craniometaphyseal dysplasia, erythrokeratodermia variabilis et progressiva 3, erythrokeratodermia variabilis.

BP4

Computational evidence support a benign effect (MetaRNN=0.004578203).

BP6

Variant 6-121447605-C-T is Benign according to our data. Variant chr6-121447605-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-121447605-C-T is described in Lovd as [Benign]. Variant chr6-121447605-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00912 (1384/151782) while in subpopulation NFE AF= 0.0161 (1092/67892). AF 95% confidence interval is 0.0153. There are 10 homozygotes in gnomad4. There are 617 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA1	NM_000165.5 link	c.758C>T	p.Ala253Val	missense_variant	Exon 2 of 2	ENST00000282561.4	NP_000156.1	P17302A0A654IBU3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GJA1	ENST00000282561.4 link	c.758C>T	p.Ala253Val	missense_variant	Exon 2 of 2	1	NM_000165.5	ENSP00000282561.3	P17302
GJA1	ENST00000647564.1 link	c.758C>T	p.Ala253Val	missense_variant	Exon 2 of 2			ENSP00000497565.1	P17302
GJA1	ENST00000649003.1 link	c.758C>T	p.Ala253Val	missense_variant	Exon 2 of 2			ENSP00000497283.1	P17302
GJA1	ENST00000650427.1 link	c.758C>T	p.Ala253Val	missense_variant	Exon 2 of 2			ENSP00000497367.1	P17302

Frequencies

GnomAD3 genomes

AF:

0.00915

AC:

1388

AN:

151664

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00286

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00761

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.000417

Gnomad FIN

AF:

0.00265

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0161

Gnomad OTH

AF:

0.0111

GnomAD3 exomes

AF:

0.00809

AC:

2035

AN:

251464

Hom.:

AF XY:

0.00823

AC XY:

1119

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00792

Gnomad ASJ exome

AF:

0.00218

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00108

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.00863

GnomAD4 exome

AF:

0.0136

AC:

19895

AN:

1461780

Hom.:

199

Cov.:

AF XY:

0.0133

AC XY:

9690

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00263

Gnomad4 AMR exome

AF:

0.00780

Gnomad4 ASJ exome

AF:

0.00230

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00110

Gnomad4 FIN exome

AF:

0.00268

Gnomad4 NFE exome

AF:

0.0165

Gnomad4 OTH exome

AF:

0.0136

GnomAD4 genome

AF:

0.00912

AC:

1384

AN:

151782

Hom.:

Cov.:

AF XY:

0.00832

AC XY:

617

AN XY:

74162

show subpopulations

Gnomad4 AFR

AF:

0.00285

Gnomad4 AMR

AF:

0.00747

Gnomad4 ASJ

AF:

0.00116

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.000418

Gnomad4 FIN

AF:

0.00265

Gnomad4 NFE

AF:

0.0161

Gnomad4 OTH

AF:

0.0110

Alfa

AF:

0.0124

Hom.:

Bravo

AF:

0.0101

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0176

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0160

AC:

138

ExAC

AF:

0.00784

AC:

952

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0160

EpiControl

AF:

0.0152

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	GJA1: PM5, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Oculodentodigital dysplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Oculodentodigital dysplasia, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 02, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.30

T;T;T;T;T

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.53

.;.;.;.;T

MetaRNN

Benign

0.0046

T;T;T;T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

0.0

N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.82

.;.;N;.;.

REVEL

Benign

0.26

Sift

Benign

0.17

.;.;T;.;.

Sift4G

Benign

0.24

.;.;T;.;.

Polyphen

0.0080

B;B;B;B;B

Vest4

0.12

MVP

0.94

MPC

0.49

ClinPred

0.0070

GERP RS

3.9

Varity_R

0.051

gMVP

0.54

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