rs764670582

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2PP5

The NM_000165.5(GJA1):​c.716G>A​(p.Arg239Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R239R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

GJA1
NM_000165.5 missense

Scores

2
6
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 9.60

Publications

10 publications found
Variant links:
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP2
Missense variant in the GJA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.2784 (below the threshold of 3.09). Trascript score misZ: 3.3775 (above the threshold of 3.09). GenCC associations: The gene is linked to craniometaphyseal dysplasia, autosomal recessive, erythrokeratodermia variabilis et progressiva 3, oculodentodigital dysplasia, autosomal dominant palmoplantar keratoderma and congenital alopecia, hypoplastic left heart syndrome 1, craniometaphyseal dysplasia, syndactyly type 3, oculodentodigital dysplasia, autosomal recessive, nonsyndromic genetic hearing loss, Hallermann-Streiff syndrome, erythrokeratodermia variabilis.
PP5
Variant 6-121447563-G-A is Pathogenic according to our data. Variant chr6-121447563-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 64622.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GJA1NM_000165.5 linkc.716G>A p.Arg239Gln missense_variant Exon 2 of 2 ENST00000282561.4 NP_000156.1 P17302A0A654IBU3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJA1ENST00000282561.4 linkc.716G>A p.Arg239Gln missense_variant Exon 2 of 2 1 NM_000165.5 ENSP00000282561.3 P17302
GJA1ENST00000647564.1 linkc.716G>A p.Arg239Gln missense_variant Exon 2 of 2 ENSP00000497565.1 P17302
GJA1ENST00000649003.1 linkc.716G>A p.Arg239Gln missense_variant Exon 2 of 2 ENSP00000497283.1 P17302
GJA1ENST00000650427.1 linkc.716G>A p.Arg239Gln missense_variant Exon 2 of 2 ENSP00000497367.1 P17302

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
151996
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000480
GnomAD2 exomes
AF:
0.0000239
AC:
6
AN:
251460
AF XY:
0.0000294
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461800
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
727208
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.0000894
AC:
4
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86256
European-Finnish (FIN)
AF:
0.0000375
AC:
2
AN:
53402
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111946
Other (OTH)
AF:
0.00
AC:
0
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152112
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74352
show subpopulations
African (AFR)
AF:
0.0000482
AC:
2
AN:
41504
American (AMR)
AF:
0.000131
AC:
2
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5160
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4810
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10590
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67984
Other (OTH)
AF:
0.000475
AC:
1
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.517
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Jul 24, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Craniometaphyseal dysplasia, autosomal recessive Pathogenic:1
Jan 01, 2013
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Oculodentodigital dysplasia, autosomal recessive Uncertain:1
Jul 14, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GJA1 protein function. ClinVar contains an entry for this variant (Variation ID: 64622). This missense change has been observed in individual(s) with craniometaphyseal dysplasia (PMID: 23951358). This variant is present in population databases (rs764670582, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 239 of the GJA1 protein (p.Arg239Gln). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
0.13
CADD
Benign
23
DANN
Benign
0.70
DEOGEN2
Benign
0.39
T;T;T;T;T
Eigen
Benign
-0.089
Eigen_PC
Benign
0.087
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.77
.;.;.;.;T
M_CAP
Pathogenic
0.48
D
MetaRNN
Uncertain
0.56
D;D;D;D;D
MetaSVM
Uncertain
0.34
D
MutationAssessor
Benign
1.6
L;L;L;L;L
PhyloP100
9.6
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.52
.;.;N;.;.
REVEL
Uncertain
0.51
Sift
Benign
0.62
.;.;T;.;.
Sift4G
Benign
0.71
.;.;T;.;.
Polyphen
0.079
B;B;B;B;B
Vest4
0.57
MutPred
0.46
Gain of ubiquitination at K243 (P = 0.0213);Gain of ubiquitination at K243 (P = 0.0213);Gain of ubiquitination at K243 (P = 0.0213);Gain of ubiquitination at K243 (P = 0.0213);Gain of ubiquitination at K243 (P = 0.0213);
MVP
0.98
MPC
0.57
ClinPred
0.48
T
GERP RS
5.5
Varity_R
0.082
gMVP
0.72
Mutation Taster
=53/47
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs764670582; hg19: chr6-121768709; COSMIC: COSV99246793; API