Variant chr1-228158992-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020435.4(GJC2):c.1234C>T(p.His412Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000956 in 1,603,620 control chromosomes in the GnomAD database, including 3 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00096 ( 3 hom. )

Consequence

GJC2
NM_020435.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10B:2

Conservation

PhyloP100: 4.83

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.089141846).

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJC2	NM_020435.4 link	c.1234C>T	p.His412Tyr	missense_variant	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.1234C>T	p.His412Tyr	missense_variant	Exon 2 of 2	1	NM_020435.4	ENSP00000355675.2		Q5T442

Frequencies

GnomAD3 genomes

AF:

0.000927

AC:

141

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00178

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000748

AC:

169

AN:

225966

Hom.:

AF XY:

0.000719

AC XY:

AN XY:

125230

show subpopulations

Gnomad AFR exome

AF:

0.0000805

Gnomad AMR exome

AF:

0.000238

Gnomad ASJ exome

AF:

0.000629

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000681

Gnomad FIN exome

AF:

0.000428

Gnomad NFE exome

AF:

0.00141

Gnomad OTH exome

AF:

0.000715

GnomAD4 exome

AF:

0.000959

AC:

1392

AN:

1451458

Hom.:

Cov.:

AF XY:

0.000938

AC XY:

677

AN XY:

721648

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000225

Gnomad4 ASJ exome

AF:

0.000655

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.000801

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.000920

GnomAD4 genome

AF:

0.000927

AC:

141

AN:

152162

Hom.:

Cov.:

AF XY:

0.000700

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00178

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00129

Hom.:

Bravo

AF:

0.000971

ExAC

AF:

0.000797

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

May 11, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 15, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in individual with segmental dystonia, spasticity, and hypomyelination who also harbored 2 additional GJC2 variants (Zittel et al., 2012); Published functional studies demonstrate impaired transfer of Lucifer yellow dye in cells transfected with H412Y (described as H409Y), supporting altered gap junction function (Finegold et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22351697, 29906362, 22833003) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GJC2 c.1234C>T; p.His412Tyr variant (rs200334298), also known as H409Y, is reported in the literature in individuals affected with vascular and lymphatic malformations (Finegold 2012, Michelini 2016, Serio 2022). Additionally, this variant has been reported in an individual with Pelizaeus-Merzbacher-like disease, a form of hypomyelinating leukodystrophy (Zittel 2012). This variant is found in the non-Finnish European population with an allele frequency of 0.1402% (161/114,842 alleles) in the Genome Aggregation Database. Functional analyses of the variant protein show impaired function (Finegold 2012). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.5). 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: Finegold DN et al. Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment. Clin Cancer Res. 2012 Apr 15;18(8):2382-90. PMID: 22351697. Michelini S et al. Genetic Screening in a Large Cohort of Italian Patients Affected by Primary Lymphedema Using a Next Generation Sequencing (NGS) Approach. Lymphology. 2016 Jun;49(2):57-72. PMID: 29906362. Serio VB et al. Nosological and Theranostic Approach to Vascular Malformation through cfDNA NGS Liquid Biopsy. J Clin Med. 2022 Jun 28;11(13):3740. PMID: 35807022. Zittel S et al. "Pelizaeus-Merzbacher-like disease" presenting as complicated hereditary spastic paraplegia. J Neurol. 2012 Nov;259(11):2498-500. PMID: 22833003. -

not specified

Uncertain:1

Jul 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GJC2 c.1234C>T (p.His412Tyr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 225966 control chromosomes (genomAD). c.1234C>T has been reported in the literature in individuals affected with lymphedema or PelizaeusMerzbacher-like disease (Finegold_2012, Zittel_2012, Michelini_2016). These reports do not provide unequivocal conclusions about association of the variant with Hypomyelinating Leukodystrophy 2. At least one functional study reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Finegold_2012). Seven ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. The following publications have been ascertained in the context of this evaluation (PMID: 22351697, 29906362, 35807022, 22833003). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Spastic paraplegia

Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 412 of the GJC2 protein (p.His412Tyr). This variant is present in population databases (rs200334298, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with lymphedema and/or Pelizaeus-Merzbacher-like disease (PMID: 22351697, 22833003, 29906362). This variant is also known as H409Y. ClinVar contains an entry for this variant (Variation ID: 445910). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJC2 protein function. Experimental studies have shown that this missense change affects GJC2 function (PMID: 22351697). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Sep 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1234C>T (p.H412Y) alteration is located in exon 2 (coding exon 1) of the GJC2 gene. This alteration results from a C to T substitution at nucleotide position 1234, causing the histidine (H) at amino acid position 412 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia

Uncertain:1

Mar 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypomyelinating leukodystrophy 2

Uncertain:1

Feb 11, 2021

Molecular Diagnostics Lab, Nemours Children's Health, Delaware

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant (c.1234C>T, p.His214Tyr) has been observed at very low frequency in population databases. It has been reported in the literature (PMID:22351697, PMID 22833003). Variant prediction programs provide no consensus as to the pathogenicity of the variant, and no functional studies have been published. -

Hypomyelinating leukodystrophy 2;C2750784:Hereditary spastic paraplegia 44;C4747646:Lymphatic malformation 3

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.16

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.58

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.36

M_CAP

Benign

0.046

MetaRNN

Benign

0.089

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

0.34

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.81

REVEL

Uncertain

0.50

Sift

Benign

0.037

Sift4G

Uncertain

0.058

Polyphen

0.10

Vest4

0.71

MVP

0.93

ClinPred

0.047

GERP RS

2.9

Varity_R

0.16

gMVP

0.12

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