rs878853083

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_020435.4(GJC2):c.17G>A(p.Trp6*) 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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
lymphatic malformation 3
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P
hereditary spastic paraplegia 44
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
lymphatic malformation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GJC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 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 78 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 235629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJC2	NM_020435.4 link	c.17G>A	p.Trp6*	stop_gained	Exon 2 of 2	ENST00000366714.3	NP_065168.2	Q5T442A0A654IBV7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJC2	ENST00000366714.3 link	c.17G>A	p.Trp6*	stop_gained	Exon 2 of 2	1	NM_020435.4	ENSP00000355675.2		Q5T442

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

19592

American (AMR)

AF:

0.00

AC:

AN:

27672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14298

East Asian (EAS)

AF:

0.00

AC:

AN:

11086

South Asian (SAS)

AF:

0.00

AC:

AN:

71128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2632

European-Non Finnish (NFE)

AF:

0.00000145

AC:

AN:

687752

Other (OTH)

AF:

0.00

AC:

AN:

32888

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000165

AC:

AN:

121398

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

56136

show subpopulations

African (AFR)

AF:

0.0000628

AC:

AN:

31856

American (AMR)

AF:

0.00

AC:

AN:

9080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3266

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.00

AC:

AN:

3588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

200

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62332

Other (OTH)

AF:

0.00

AC:

AN:

1682

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

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

Apr 15, 2021

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 11, 2016

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

1.0

PhyloP100

9.6

Vest4

0.66

GERP RS

3.1

Mutation Taster

=19/181

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over