rs17653265

chr6-121447605-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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. 12/19 in silico tools predict 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. A253A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0091 (10 hom., cov: 32)
  • Exomes 𝑓: 0.014 (199 hom.)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.78

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GJA1
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA1	NM_000165.5	c.758C>T	p.Ala253Val	missense_variant	2/2	ENST00000282561.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA1	ENST00000282561.4	c.758C>T	p.Ala253Val	missense_variant	2/2	1	NM_000165.5	P1
GJA1	ENST00000647564.1	c.758C>T	p.Ala253Val	missense_variant	2/2			P1
GJA1	ENST00000649003.1	c.758C>T	p.Ala253Val	missense_variant	2/2			P1
GJA1	ENST00000650427.1	c.758C>T	p.Ala253Val	missense_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.00915 AC: 1388 AN: 151664 Hom.: 10 Cov.: 32

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.: 23 AF XY: 0.00823 AC XY: 1119 AN XY: 135906

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.: 33 AF XY: 0.0133 AC XY: 9690 AN XY: 727196

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.: 10 Cov.: 32 AF XY: 0.00832 AC XY: 617 AN XY: 74162

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.: 5

Bravo AF: 0.0101

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0176 AC: 68

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0160 AC: 138

ExAC AF: 0.00784 AC: 952

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0160

EpiControl AF: 0.0152

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -

not provided Benign:2

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 -

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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	16
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	D
MetaRNN	Benign	0.0046	T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.0	N;N;N;N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
Polyphen		0.0080	B;B;B;B;B
Vest4		0.12
MVP		0.94
MPC		0.49
ClinPred		0.0070	T
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

Other links and lift over

dbSNP: rs17653265; hg19: chr6-121768751; COSMIC: COSV99031377;