rs57946868

Variant names:

• chr6-121447564-G-A
• rs57946868
• NM_000165.5:c.717G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-121447564-G-A
• chr6-121447564-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000165.5(GJA1):​c.717G>A​(p.Arg239Arg) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.03
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• hypoplastic left heart syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• oculodentodigital dysplasia

  Inheritance: AD, SD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant palmoplantar keratoderma and congenital alopecia

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, G2P
• erythrokeratodermia variabilis et progressiva 3

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• oculodentodigital dysplasia, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• craniometaphyseal dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• erythrokeratodermia variabilis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• syndactyly type 3

  Inheritance: AD, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Hallermann-Streiff syndrome

  Inheritance: AR Classification: LIMITED Submitted by: G2P
• craniometaphyseal dysplasia, autosomal recessive

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 137482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000165.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA1	NM_000165.5	MANE Select	c.717G>A	p.Arg239Arg	synonymous	Exon 2 of 2	NP_000156.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA1	ENST00000282561.4	TSL:1 MANE Select	c.717G>A	p.Arg239Arg	synonymous	Exon 2 of 2	ENSP00000282561.3
	GJA1	ENST00000647564.1		c.717G>A	p.Arg239Arg	synonymous	Exon 2 of 2	ENSP00000497565.1
	GJA1	ENST00000649003.1		c.717G>A	p.Arg239Arg	synonymous	Exon 2 of 2	ENSP00000497283.1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4681 AN: 151952 Hom.: 145 Cov.: 32

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

GnomAD2 exomes AF: 0.0174 AC: 4387 AN: 251464 AF XY: 0.0172

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 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.: 33 AF XY: 0.0155 AC XY: 11294 AN XY: 727208

African (AFR) AF: 0.0824 AC: 2758 AN: 33474

American (AMR) AF: 0.0100 AC: 448 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 282 AN: 26134

East Asian (EAS) AF: 0.00123 AC: 49 AN: 39700

South Asian (SAS) AF: 0.0337 AC: 2911 AN: 86258

European-Finnish (FIN) AF: 0.00468 AC: 250 AN: 53414

Middle Eastern (MID) AF: 0.0192 AC: 111 AN: 5768

European-Non Finnish (NFE) AF: 0.0127 AC: 14168 AN: 1111930

Other (OTH) AF: 0.0185 AC: 1120 AN: 60394

GnomAD4 genome AF: 0.0308 AC: 4684 AN: 152070 Hom.: 145 Cov.: 32 AF XY: 0.0308 AC XY: 2293 AN XY: 74340

African (AFR) AF: 0.0781 AC: 3240 AN: 41460

American (AMR) AF: 0.0157 AC: 240 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.00233 AC: 12 AN: 5158

South Asian (SAS) AF: 0.0362 AC: 174 AN: 4804

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10596

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0130 AC: 883 AN: 67990

Other (OTH) AF: 0.0237 AC: 50 AN: 2106

Alfa AF: 0.0136 Hom.: 29

Bravo AF: 0.0328

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.0139

EpiControl AF: 0.0123

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	Hypoplastic left heart syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	Oculodentodigital dysplasia (1)
-	-	1	Oculodentodigital dysplasia, autosomal recessive (1)
-	-	1	Syndactyly type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.32
DANN	Benign	0.29
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs57946868; hg19: chr6-121768710; COSMIC: COSV107293691;