rs140942230

Positions:

• chr1-228158951-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 1.83

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]

ACMG classification

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=5, Uncertain_significance=3}. 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	Protein	UniProt
GJC2	NM_020435.4	c.1193C>T	p.Thr398Ile	missense_variant	2/2	ENST00000366714.3	NP_065168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJC2	ENST00000366714.3	c.1193C>T	p.Thr398Ile	missense_variant	2/2	1	NM_020435.4	ENSP00000355675.2

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152156 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00161 AC XY: 164 AN XY: 102062

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.: 5 Cov.: 33 AF XY: 0.00179 AC XY: 1260 AN XY: 705054

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.: 0 Cov.: 32 AF XY: 0.000980 AC XY: 73 AN XY: 74456

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.: 0

Bravo AF: 0.00135

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ExAC AF: 0.00117 AC: 131

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 27, 2022	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 13, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	GJC2: BS1 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 18, 2024

Variant summary: GJC2 c.1193C>T (p.Thr398Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 183130 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GJC2 causing Hypomyelinating Leukodystrophy 2, allowing no conclusion about variant significance. c.1193C>T has been reported in the literature in heterozygous individuals affected with Hypomyelinating Leukodystrophy 2 (Henneke_2008). However, no co-occurring variants were identified in these individuals. These report(s) do not provide unequivocal conclusions about association of the variant with Hypomyelinating Leukodystrophy 2. At least two publications report experimental evidence evaluating an impact on protein function. These results were conflicting, with one report showing no damaging effect of this variant (Kim_2013) and one report suggesting aberrant channel activity (Diekmann_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20442743, 18094336, 23544880). ClinVar contains an entry for this variant (Variation ID: 241296). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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, no assertion criteria provided

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	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	15
DANN	Benign	0.15
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.58
Sift	Benign	0.54	T
Sift4G	Benign	0.29	T
Polyphen		0.012	B
Vest4		0.64
MVP		0.82
ClinPred		0.0025	T
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

Other links and lift over

dbSNP: rs140942230; hg19: chr1-228346652; COSMIC: COSV105281669;