1-228158211-CGAGGAG-CGAG

Variant names:

• chr1-228158211-CGAG-C
• rs746050475
• NM_020435.4:c.472_474delGAG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_020435.4(GJC2):​c.472_474delGAG​(p.Glu158del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00534 in 1,328,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (0 hom.)
• Consequence: GJC2 NM_020435.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 9.06

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 1-228158211-CGAG-C is Benign according to our data. Variant chr1-228158211-CGAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 811586.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chr1-228158211-CGAG-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00599 (7063/1178354) while in subpopulation AMR AF= 0.0311 (737/23672). AF 95% confidence interval is 0.0293. There are 0 homozygotes in gnomad4_exome. There are 3866 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJC2	NM_020435.4	c.472_474delGAG	p.Glu158del	conservative_inframe_deletion	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.472_474delGAG	p.Glu158del	conservative_inframe_deletion	Exon 2 of 2	1	NM_020435.4	ENSP00000355675.2

Frequencies

GnomAD3 genomes AF: 0.000187 AC: 28 AN: 149912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000729

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000513

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000208

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00599 AC: 7063 AN: 1178354 Hom.: 0 AF XY: 0.00677 AC XY: 3866 AN XY: 570674

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.0311

Gnomad4 ASJ exome AF: 0.0168

Gnomad4 EAS exome AF: 0.0144

Gnomad4 SAS exome AF: 0.0179

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.00394

Gnomad4 OTH exome AF: 0.00741

GnomAD4 genome AF: 0.000187 AC: 28 AN: 149988 Hom.: 0 Cov.: 32 AF XY: 0.000219 AC XY: 16 AN XY: 73200

Gnomad4 AFR AF: 0.0000727

Gnomad4 AMR AF: 0.000133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.000513

Gnomad4 NFE AF: 0.000208

Gnomad4 OTH AF: 0.00

Asia WGS AF: 0.00783 AC: 27 AN: 3464

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 22, 2019

This sequence change deletes 3 nucleotides from exon 2 of the GJC2 mRNA (c.472_474delGAG). This leads to the deletion of 1 amino acid residue in the GJC2 protein (p.Glu158del) but otherwise preserves the integrity of the reading frame. While this variant is present in population databases (rs746050475), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a GJC2-related disease. In summary, this is a rare single amino acid deletion with uncertain impact on protein function. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

GJC2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2023

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

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: rs746050475; hg19: chr1-228345912;