rs2232191

Positions:

• chr1-147758870-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_181703.4(GJA5):​c.369C>T​(p.Tyr123Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00659 in 1,614,154 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (72 hom.)
• Consequence: GJA5 NM_181703.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.00500

Genes affected

GJA5 (HGNC:4279): (gap junction protein alpha 5) 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. Mutations in this gene may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described. [provided by RefSeq, Jul 2008]

LOC102723321 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-147758870-G-A is Benign according to our data. Variant chr1-147758870-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 292449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-147758870-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.005 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00663 (1009/152300) while in subpopulation EAS AF= 0.0515 (266/5168). AF 95% confidence interval is 0.0464. There are 13 homozygotes in gnomad4. There are 498 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1009 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA5	NM_181703.4	c.369C>T	p.Tyr123Tyr	synonymous_variant	2/2	ENST00000579774.3	NP_859054.1
GJA5	NM_005266.7	c.369C>T	p.Tyr123Tyr	synonymous_variant	2/2		NP_005257.2
LOC102723321	XR_922079.4	n.82-18691G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA5	ENST00000579774.3	c.369C>T	p.Tyr123Tyr	synonymous_variant	2/2	1	NM_181703.4	ENSP00000463851.1
GJA5	ENST00000621517.1	c.369C>T	p.Tyr123Tyr	synonymous_variant	2/2	2		ENSP00000484552.1
GJA5	ENST00000430508.1	c.369C>T	p.Tyr123Tyr	synonymous_variant	2/2	2		ENSP00000407645.1

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 1011 AN: 152182 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0515

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00628

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00920 AC: 2311 AN: 251114 Hom.: 30 AF XY: 0.00925 AC XY: 1256 AN XY: 135722

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.00651

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.0484

Gnomad SAS exome AF: 0.00820

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00639

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00658 AC: 9625 AN: 1461854 Hom.: 72 Cov.: 33 AF XY: 0.00673 AC XY: 4893 AN XY: 727234

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00660

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.0384

Gnomad4 SAS exome AF: 0.00844

Gnomad4 FIN exome AF: 0.00163

Gnomad4 NFE exome AF: 0.00538

Gnomad4 OTH exome AF: 0.00871

GnomAD4 genome AF: 0.00663 AC: 1009 AN: 152300 Hom.: 13 Cov.: 32 AF XY: 0.00669 AC XY: 498 AN XY: 74456

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.0515

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00628

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00731 Hom.: 5

Bravo AF: 0.00735

EpiCase AF: 0.00791

EpiControl AF: 0.00859

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2019	This variant is associated with the following publications: (PMID: 22713807) -

Familial atrial fibrillation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Atrial fibrillation, familial, 11;C4551959:Atrial standstill 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.96
DANN	Benign	0.75

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: rs2232191; hg19: chr1-147230978; COSMIC: COSV54783140; COSMIC: COSV54783140;