1-228158211-CGAGGAG-CGAG

Variant summary

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

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

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]

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 rank MANE Protein UniProt
GJC2NM_020435.4 linkc.472_474delGAG p.Glu158del conservative_inframe_deletion Exon 2 of 2 ENST00000366714.3 NP_065168.2 Q5T442A0A654IBV7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJC2ENST00000366714.3 linkc.472_474delGAG p.Glu158del conservative_inframe_deletion Exon 2 of 2 1 NM_020435.4 ENSP00000355675.2 Q5T442

Frequencies

GnomAD3 genomes
AF:
0.000187
AC:
28
AN:
149912
Hom.:
0
Cov.:
32
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.:
0
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:
28
AN:
149988
Hom.:
0
Cov.:
32
AF XY:
0.000219
AC XY:
16
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:
27
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
Mar 22, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

GJC2-related disorder Benign:1
Dec 06, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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). -

not provided Benign:1
Nov 29, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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.

Other links and lift over

dbSNP: rs746050475; hg19: chr1-228345912; API