rs57946868

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000165.5(GJA1):c.717G>A(p.Arg239=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,613,866 control chromosomes in the GnomAD database, including 431 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R239R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.031 ( 145 hom., cov: 32)

Exomes 𝑓: 0.015 ( 286 hom. )

Consequence

GJA1
NM_000165.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -3.03

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 6-121447564-G-A is Benign according to our data. Variant chr6-121447564-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 137482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-121447564-G-A is described in Lovd as [Benign]. Variant chr6-121447564-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-3.03 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA1	NM_000165.5 linkuse as main transcript	c.717G>A	p.Arg239=	synonymous_variant	2/2	ENST00000282561.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
GJA1	ENST00000282561.4 linkuse as main transcript	c.717G>A	p.Arg239=	synonymous_variant	2/2	1	NM_000165.5	P1
GJA1	ENST00000647564.1 linkuse as main transcript	c.717G>A	p.Arg239=	synonymous_variant	2/2			P1
GJA1	ENST00000649003.1 linkuse as main transcript	c.717G>A	p.Arg239=	synonymous_variant	2/2			P1
GJA1	ENST00000650427.1 linkuse as main transcript	c.717G>A	p.Arg239=	synonymous_variant	2/2			P1

Frequencies

GnomAD3 genomes

AF:

0.0308

AC:

4681

AN:

151952

Hom.:

145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0783

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0157

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.0362

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.0240

GnomAD3 exomes

AF:

0.0174

AC:

4387

AN:

251464

Hom.:

AF XY:

0.0172

AC XY:

2339

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0831

Gnomad AMR exome

AF:

0.00919

Gnomad ASJ exome

AF:

0.00923

Gnomad EAS exome

AF:

0.00190

Gnomad SAS exome

AF:

0.0324

Gnomad FIN exome

AF:

0.00397

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.0151

AC:

22097

AN:

1461796

Hom.:

286

Cov.:

AF XY:

0.0155

AC XY:

11294

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0824

Gnomad4 AMR exome

AF:

0.0100

Gnomad4 ASJ exome

AF:

0.0108

Gnomad4 EAS exome

AF:

0.00123

Gnomad4 SAS exome

AF:

0.0337

Gnomad4 FIN exome

AF:

0.00468

Gnomad4 NFE exome

AF:

0.0127

Gnomad4 OTH exome

AF:

0.0185

GnomAD4 genome

AF:

0.0308

AC:

4684

AN:

152070

Hom.:

145

Cov.:

AF XY:

0.0308

AC XY:

2293

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0781

Gnomad4 AMR

AF:

0.0157

Gnomad4 ASJ

AF:

0.0138

Gnomad4 EAS

AF:

0.00233

Gnomad4 SAS

AF:

0.0362

Gnomad4 FIN

AF:

0.00283

Gnomad4 NFE

AF:

0.0130

Gnomad4 OTH

AF:

0.0237

Alfa

AF:

0.00918

Hom.:

Bravo

AF:

0.0328

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0139

EpiControl

AF:

0.0123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 07, 2014	- -

Oculodentodigital dysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Syndactyly type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Oculodentodigital dysplasia, autosomal recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hypoplastic left heart syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

Cadd

Benign

0.32

Dann

Benign

0.29

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