1-147758653-A-C

Position:

• chr1-147758653-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000579774.3(GJA5):​c.586T>G​(p.Cys196Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GJA5 ENST00000579774.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA5	NM_181703.4	c.586T>G	p.Cys196Gly	missense_variant	2/2	ENST00000579774.3	NP_859054.1
LOC102723321	XR_922079.4	n.82-18908A>C		intron_variant, non_coding_transcript_variant
GJA5	NM_005266.7	c.586T>G	p.Cys196Gly	missense_variant	2/2		NP_005257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA5	ENST00000579774.3	c.586T>G	p.Cys196Gly	missense_variant	2/2	1	NM_181703.4	ENSP00000463851	P1
GJA5	ENST00000621517.1	c.586T>G	p.Cys196Gly	missense_variant	2/2	2		ENSP00000484552	P1
GJA5	ENST00000430508.1	c.586T>G	p.Cys196Gly	missense_variant	2/2	2		ENSP00000407645

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, University of Leuven

Apr 30, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.0	H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-12	.;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D
Sift4G	Uncertain	0.0040	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.94
MutPred		0.91		Loss of stability (P = 0.0036);Loss of stability (P = 0.0036);Loss of stability (P = 0.0036);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.99

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: rs1553226930; hg19: chr1-147230761;