rs74315313
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_020435.4(GJC2):c.718C>T(p.Arg240Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
GJC2
NM_020435.4 stop_gained
NM_020435.4 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 1.49
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 20 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-228158476-C-T is Pathogenic according to our data. Variant chr1-228158476-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2074.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-228158476-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GJC2 | NM_020435.4 | c.718C>T | p.Arg240Ter | stop_gained | 2/2 | ENST00000366714.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GJC2 | ENST00000366714.3 | c.718C>T | p.Arg240Ter | stop_gained | 2/2 | 1 | NM_020435.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151904Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1459868Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 726332
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151904Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74198
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hypomyelinating leukodystrophy 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a pathogenic variant in a 4-year-old male with intellectual disability, hypotonia, spasticity, wide-based gait, significantly delayed myelination, nystagmus, cerebral palsy - |
not provided Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A
Vest4
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at