Variant 1-228158211-CGAGGAG-CGAG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1

The NM_020435.4(GJC2):c.472_474del(p.Glu158del) variant causes a 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 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 9.06

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 -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/exons	MANE	UniProt
GJC2	NM_020435.4 linkuse as main transcript	c.472_474del	p.Glu158del	inframe_deletion	2/2	ENST00000366714.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJC2	ENST00000366714.3 linkuse as main transcript	c.472_474del	p.Glu158del	inframe_deletion	2/2	1	NM_020435.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000187

AC:

AN:

149912

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00677

AC XY:

3866

AN XY:

570674

show subpopulations

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:

AN:

149988

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

AN XY:

73200

show subpopulations

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:

AN:

3464

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 22, 2019

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. 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. 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. 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, criteria provided, single submitter

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

Name

Calibrated prediction

Score

Prediction

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