rs201796910

Variant names:

• chr1-228158286-G-A
• rs201796910
• NM_020435.4:c.528G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_020435.4(GJC2):​c.528G>A​(p.Glu176Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000679 in 1,533,678 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00094 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (8 hom.)
• Consequence: GJC2 NM_020435.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.948
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-228158286-G-A is Benign according to our data. Variant chr1-228158286-G-A is described in ClinVar as [Benign]. Clinvar id is 458297.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.948 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00094 (143/152124) while in subpopulation EAS AF = 0.0151 (78/5160). AF 95% confidence interval is 0.0124. There are 2 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJC2	NM_020435.4	c.528G>A	p.Glu176Glu	synonymous_variant	Exon 2 of 2	ENST00000366714.3	NP_065168.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJC2	ENST00000366714.3	c.528G>A	p.Glu176Glu	synonymous_variant	Exon 2 of 2	1	NM_020435.4	ENSP00000355675.2

Frequencies

GnomAD3 genomes AF: 0.000921 AC: 140 AN: 152008 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0145

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00172 AC: 236 AN: 137028 AF XY: 0.00178

Gnomad AFR exome AF: 0.000275

Gnomad AMR exome AF: 0.000285

Gnomad ASJ exome AF: 0.000127

Gnomad EAS exome AF: 0.0135

Gnomad FIN exome AF: 0.00173

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000725

GnomAD4 exome AF: 0.000650 AC: 898 AN: 1381554 Hom.: 8 Cov.: 36 AF XY: 0.000686 AC XY: 467 AN XY: 680844

African (AFR) AF: 0.000127 AC: 4 AN: 31450

American (AMR) AF: 0.000140 AC: 5 AN: 35604

Ashkenazi Jewish (ASJ) AF: 0.000161 AC: 4 AN: 24832

East Asian (EAS) AF: 0.0109 AC: 386 AN: 35572

South Asian (SAS) AF: 0.00190 AC: 151 AN: 79444

European-Finnish (FIN) AF: 0.00184 AC: 71 AN: 38504

Middle Eastern (MID) AF: 0.000443 AC: 2 AN: 4516

European-Non Finnish (NFE) AF: 0.000207 AC: 222 AN: 1074212

Other (OTH) AF: 0.000923 AC: 53 AN: 57420

GnomAD4 genome AF: 0.000940 AC: 143 AN: 152124 Hom.: 2 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74376

African (AFR) AF: 0.000241 AC: 10 AN: 41562

American (AMR) AF: 0.000523 AC: 8 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3464

East Asian (EAS) AF: 0.0151 AC: 78 AN: 5160

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00161 AC: 17 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000518 Hom.: 0

Bravo AF: 0.00105

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.60
DANN	Benign	0.32
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs201796910; hg19: chr1-228345987;