1-147758874-G-C

Variant names:

• chr1-147758874-G-C
• rs781831348
• NM_181703.4:c.365C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_181703.4(GJA5):​c.365C>G​(p.Ser122Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S122F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GJA5 NM_181703.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98
• Publications: 0 publications found

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]

GJA5 Gene-Disease associations (from GenCC):

• atrial fibrillation, familial, 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000294222 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: 1.5546 (below the threshold of 3.09). GenCC associations: The gene is linked to heart conduction disease, atrial fibrillation, familial, 11, familial atrial fibrillation, congenital heart disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181703.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA5	NM_181703.4	MANE Select	c.365C>G	p.Ser122Cys	missense	Exon 2 of 2	NP_859054.1	P36382
	GJA5	NM_005266.7		c.365C>G	p.Ser122Cys	missense	Exon 2 of 2	NP_005257.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA5	ENST00000579774.3	TSL:1 MANE Select	c.365C>G	p.Ser122Cys	missense	Exon 2 of 2	ENSP00000463851.1	P36382
	GJA5	ENST00000621517.1	TSL:2	c.365C>G	p.Ser122Cys	missense	Exon 2 of 2	ENSP00000484552.1	P36382
	GJA5	ENST00000863529.1		c.365C>G	p.Ser122Cys	missense	Exon 2 of 2	ENSP00000533588.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251150 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Atrial fibrillation, familial, 11;C4551959:Atrial standstill 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.37
Sift	Benign	0.045	D
Sift4G	Uncertain	0.045	D
Polyphen		0.85	P
Vest4		0.21
MutPred		0.36		Loss of disorder (P = 0.0091)
MVP		0.94
ClinPred		0.67	D
GERP RS		2.9
Varity_R		0.11
gMVP		0.63
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs781831348; hg19: chr1-147230982;