chr6-121446922-G-C

Position:

• chr6-121446922-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000165.5(GJA1):​c.75G>C​(p.Trp25Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA1 NM_000165.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity CXA1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000165.5
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.995
• PP5: Variant 6-121446922-G-C is Pathogenic according to our data. Variant chr6-121446922-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 986183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-121446922-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJA1	NM_000165.5	c.75G>C	p.Trp25Cys	missense_variant	2/2	ENST00000282561.4	NP_000156.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJA1	ENST00000282561.4	c.75G>C	p.Trp25Cys	missense_variant	2/2	1	NM_000165.5	ENSP00000282561	P1
GJA1	ENST00000647564.1	c.75G>C	p.Trp25Cys	missense_variant	2/2			ENSP00000497565	P1
GJA1	ENST00000649003.1	c.75G>C	p.Trp25Cys	missense_variant	2/2			ENSP00000497283	P1
GJA1	ENST00000650427.1	c.75G>C	p.Trp25Cys	missense_variant	2/2			ENSP00000497367	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.75G>C (p.W25C) alteration is located in exon 2 (coding exon 1) of the GJA1 gene. This alteration results from a G to C substitution at nucleotide position 75, causing the tryptophan (W) at amino acid position 25 to be replaced by a cysteine (C). Based on data from the Genome Aggregation Database (gnomAD), the GJA1 c.75G>C alteration was not observed, with coverage at this position. The p.W25C alteration has been reported in two individuals with oculodentodigital dysplasia. One patient was 34 years old and developed adult-onset progressive spastic paraplegia and sensory deficits in addition to congenital features of ODDD (Furuta, 2012). The other patient had features of ODDD and a normal neurological exam at age 7 years, but white matter changes were seen on brain MRI. Parental testing confirmed his alteration arose de novo (Dwarakanathan, 2015). This amino acid position is highly conserved in available vertebrate species. The p.W25C alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;D;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	.;.;.;.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	1.0	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M;M;M;M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-11	.;.;D;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;.
Polyphen		1.0	D;D;D;D;D
Vest4		0.94
MutPred		0.93		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.97
gMVP		1.0

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: rs1773898476; hg19: chr6-121768068;