rs140942230

Positions:

chr1-228158951-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_020435.4(GJC2):c.1193C>T(p.Thr398Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,573,830 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 5 hom. )

Consequence

GJC2
NM_020435.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 1.83

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013080448).

BP6

Variant 1-228158951-C-T is Benign according to our data. Variant chr1-228158951-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241296.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2}. Variant chr1-228158951-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJC2	NM_020435.4 linkuse as main transcript	c.1193C>T	p.Thr398Ile	missense_variant	2/2	ENST00000366714.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJC2	ENST00000366714.3 linkuse as main transcript	c.1193C>T	p.Thr398Ile	missense_variant	2/2	1	NM_020435.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

165

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00149

AC:

272

AN:

183130

Hom.:

AF XY:

0.00161

AC XY:

164

AN XY:

102062

show subpopulations

Gnomad AFR exome

AF:

0.000328

Gnomad AMR exome

AF:

0.000850

Gnomad ASJ exome

AF:

0.00207

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00175

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00224

Gnomad OTH exome

AF:

0.00184

GnomAD4 exome

AF:

0.00177

AC:

2523

AN:

1421556

Hom.:

Cov.:

AF XY:

0.00179

AC XY:

1260

AN XY:

705054

show subpopulations

Gnomad4 AFR exome

AF:

0.000247

Gnomad4 AMR exome

AF:

0.000841

Gnomad4 ASJ exome

AF:

0.00181

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00184

Gnomad4 FIN exome

AF:

0.000159

Gnomad4 NFE exome

AF:

0.00198

Gnomad4 OTH exome

AF:

0.00167

GnomAD4 genome

AF:

0.00108

AC:

165

AN:

152274

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000827

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00168

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00179

Hom.:

Bravo

AF:

0.00135

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ExAC

AF:

0.00117

AC:

131

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	GJC2: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 01, 2022	The GJC2 c.1193C>T; p.Thr398Ile variant (rs140942230), to our knowledge, is not reported in the medical literature or gene specific databases in association with vascular or lymphatic malformations. This variant is reported in the literature in several heterozygous individuals affected with Pelizaeus-Merzbacher-like disease, a form of hypomyelinating leukodystrophy, although no second variant was found in these individuals and the same variant occurred in an unaffected parent (Henneke 2008). This variant is found in the general population with an allele frequency of 0.14% (305/214368 alleles) in the Genome Aggregation Database. The threonine at codon 398 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.577). Functional studies of this variant are conflicting, with one report suggesting aberrant channel activity (Diekmann 2010), and a second report indicating normal localization and activity of the variant protein (Kim 2013). While this variant is unlikely to be causative of autosomal dominant lymphatic malformations, due to limited and conflicting information, its clinical significance in recessive disease is uncertain at this time. References: Diekmann S et al. Pelizaeus-Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction. Eur J Hum Genet. 2010 Sep;18(9):985-92. PMID: 20442743. Henneke M et al. GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease. Neurology. 2008 Mar 4;70(10):748-54. PMID: 18094336. Kim MS et al. The distribution and functional properties of Pelizaeus-Merzbacher-like disease-linked Cx47 mutations on Cx47/Cx47 homotypic and Cx47/Cx43 heterotypic gap junctions. Biochem J. 2013 Jun 1;452(2):249-58. PMID: 23544880. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	This variant is associated with the following publications: (PMID: 20442743, 23544880, 18094336, 21959080) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 13, 2016	- -

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2018

- -

GJC2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Benign

0.15

DEOGEN2

Benign

0.13

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

1.6

MutationTaster

Benign

0.74

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.37

REVEL

Uncertain

0.58

Sift

Benign

0.54

Sift4G

Benign

0.29

Polyphen

0.012

Vest4

0.64

MVP

0.82

ClinPred

0.0025

GERP RS

2.9

Varity_R

0.078

gMVP

0.11

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