rs145955590
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PP5
The NM_000751.3(CHRND):c.1204G>A(p.Glu402Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,998 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000751.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHRND | NM_000751.3 | c.1204G>A | p.Glu402Lys | missense_variant | Exon 10 of 12 | ENST00000258385.8 | NP_000742.1 | |
CHRND | NM_001256657.2 | c.1159G>A | p.Glu387Lys | missense_variant | Exon 9 of 11 | NP_001243586.1 | ||
CHRND | NM_001311196.2 | c.901G>A | p.Glu301Lys | missense_variant | Exon 10 of 12 | NP_001298125.1 | ||
CHRND | NM_001311195.2 | c.622G>A | p.Glu208Lys | missense_variant | Exon 8 of 10 | NP_001298124.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000328 AC: 5AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251358Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135908
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461778Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16AN XY: 727192
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 3C Pathogenic:1
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not provided Pathogenic:1
Published functional studies demonstrate a damaging effect, as E381K has significantly reduced co-cluster formation with rapsyn than wild type (PMID: 16916845); Also known as E381K; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16916845, 37721175) -
Lethal multiple pterygium syndrome Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 402 of the CHRND protein (p.Glu402Lys). This variant is present in population databases (rs145955590, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 16916845). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 1141G>A (E381K). ClinVar contains an entry for this variant (Variation ID: 189817). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CHRND protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects CHRND function (PMID: 16916845). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Congenital myasthenic syndrome 3B Uncertain:1
The homozygous p.Glu402Lys variant in CHRND (also referred to as p.Glu381Lys) was identified by our study in 1 individual with congenital myasthenic syndrome 3B. The variant has been reported in 1 German individual with congenital myasthenic syndrome 3B (PMID: 16916845), and has been identified in 0.01% (4/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs145955590). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 189817) as pathogenic by OMIM. In vitro functional studies provide some evidence that the p.Glu402Lys variant may slightly impact protein function (PMID: 16916845). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3_supporting, PS3_supporting (Richards 2015). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at