1-228157826-T-TGGGCAAGGTGTGGC
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_020435.4(GJC2):c.69_82dupGGGCAAGGTGTGGC(p.Leu28fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000727 in 1,375,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L28L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.3e-7 ( 0 hom. )
Consequence
GJC2
NM_020435.4 frameshift
NM_020435.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.68
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 60 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-228157826-T-TGGGCAAGGTGTGGC is Pathogenic according to our data. Variant chr1-228157826-T-TGGGCAAGGTGTGGC is described in ClinVar as [Pathogenic]. Clinvar id is 2726006.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GJC2 | NM_020435.4 | c.69_82dupGGGCAAGGTGTGGC | p.Leu28fs | frameshift_variant | 2/2 | ENST00000366714.3 | NP_065168.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 7.27e-7 AC: 1AN: 1375804Hom.: 0 Cov.: 37 AF XY: 0.00000147 AC XY: 1AN XY: 682576
GnomAD4 exome
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37
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1
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682576
Gnomad4 AFR exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Spastic paraplegia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 02, 2023 | This sequence change creates a premature translational stop signal (p.Leu28Argfs*16) in the GJC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 412 amino acid(s) of the GJC2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pelizaeus-Merzbacher disease (PMID: 18094336). This variant disrupts a region of the GJC2 protein in which other variant(s) (p.Arg240*) have been determined to be pathogenic (PMID: 15192806; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.