Variant chr1-228157775-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_020435.4(GJC2):c.17G>A(p.Trp6Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000295 in 1,015,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000016 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

GJC2
NM_020435.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.63

Variant links:

Genes affected

GJC2 (HGNC:17494): (gap junction protein gamma 2) This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans. Defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1. [provided by RefSeq, Jul 2008]

GJC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-228157775-G-A is Pathogenic according to our data. Variant chr1-228157775-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 235629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJC2	NM_020435.4 linkuse as main transcript	c.17G>A	p.Trp6Ter	stop_gained	2/2	ENST00000366714.3	NP_065168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJC2	ENST00000366714.3 linkuse as main transcript	c.17G>A	p.Trp6Ter	stop_gained	2/2	1	NM_020435.4	ENSP00000355675	P1

Frequencies

GnomAD3 genomes

AF:

0.0000165

AC:

AN:

121398

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000628

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

GnomAD4 exome

AF:

0.00000112

AC:

AN:

893988

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

442100

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000145

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000165

AC:

AN:

121398

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

56136

show subpopulations

Gnomad4 AFR

AF:

0.0000628

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

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Apr 15, 2021

This nonsense variant (c.17G>A, p.Trp6*) has been observed at extremely low frequency in population databases (gnomAD). The change has not been reported in the literature and no functional studies have been published. It was found in trans with both c.282C>G (p.Tyr94*, pathogenic) and c.947C>T (p.Pro316Leu, likely benign) in an affected individual. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jan 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

1.0

MutationTaster

Benign

1.0

Vest4

0.66

GERP RS

3.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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