rs765192739

Positions:

chr6-121447451-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP2PP3_StrongPP5

The NM_000165.5(GJA1):c.604C>T(p.Arg202Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,842 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R202H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GJA1
NM_000165.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.04

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-121447452-G-A is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GJA1. . Gene score misZ 1.2784 (greater than the threshold 3.09). Trascript score misZ 3.3775 (greater than threshold 3.09). GenCC has associacion of gene with craniometaphyseal dysplasia, autosomal recessive, Hallermann-Streiff syndrome, syndactyly type 3, oculodentodigital dysplasia, nonsyndromic genetic hearing loss, hypoplastic left heart syndrome 1, autosomal dominant palmoplantar keratoderma and congenital alopecia, oculodentodigital dysplasia, autosomal recessive, craniometaphyseal dysplasia, erythrokeratodermia variabilis et progressiva 3, erythrokeratodermia variabilis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 6-121447451-C-T is Pathogenic according to our data. Variant chr6-121447451-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521097.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA1	NM_000165.5 linkuse as main transcript	c.604C>T	p.Arg202Cys	missense_variant	2/2	ENST00000282561.4	NP_000156.1	P17302A0A654IBU3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GJA1	ENST00000282561.4 linkuse as main transcript	c.604C>T	p.Arg202Cys	missense_variant	2/2	1	NM_000165.5	ENSP00000282561.3	P17302
GJA1	ENST00000647564.1 linkuse as main transcript	c.604C>T	p.Arg202Cys	missense_variant	2/2			ENSP00000497565.1	P17302
GJA1	ENST00000649003.1 linkuse as main transcript	c.604C>T	p.Arg202Cys	missense_variant	2/2			ENSP00000497283.1	P17302
GJA1	ENST00000650427.1 linkuse as main transcript	c.604C>T	p.Arg202Cys	missense_variant	2/2			ENSP00000497367.1	P17302

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152096

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251466

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74294

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2016

- -

GJA1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 02, 2023

The GJA1 c.604C>T variant is predicted to result in the amino acid substitution p.Arg202Cys. This variant was reported in the homozygous state in two siblings with typical features of oculodentodigital dysplasia (Family 2, Machado et al. 2023. PubMed ID: 36396593). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-121768597-C-T); however, this variant falls within a highly paralogous region therefore allele frequency data should be interpreted with caution. An alternative nucleotide change affecting the same amino acid (p.Arg202His) has been previously reported in individuals with oculodentodigital dysplasia (Paznekas et al. 2003. PubMed ID: 12457340; Fenwick et al. 2008. PubMed ID: 18946008; Shibayama et al. 2005. PubMed ID: 15879313). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;D;D

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

.;.;.;.;D

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;H;H;H;H

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.4

.;.;D;.;.

REVEL

Pathogenic

0.90

Sift

Uncertain

0.017

.;.;D;.;.

Sift4G

Pathogenic

0.0

.;.;D;.;.

Polyphen

1.0

D;D;D;D;D

Vest4

0.94

MutPred

0.87

Gain of catalytic residue at T204 (P = 0.0648);Gain of catalytic residue at T204 (P = 0.0648);Gain of catalytic residue at T204 (P = 0.0648);Gain of catalytic residue at T204 (P = 0.0648);Gain of catalytic residue at T204 (P = 0.0648);

MVP

0.99

MPC

1.6

ClinPred

1.0

GERP RS

5.0

Varity_R

0.81

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over