rs1057518958
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000751.3(CHRND):c.822delT(p.Ser274ArgfsTer52) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,716 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
CHRND
NM_000751.3 frameshift, splice_region
NM_000751.3 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.34
Genes affected
CHRND (HGNC:1965): (cholinergic receptor nicotinic delta subunit) The acetylcholine receptor of muscle has 5 subunits of 4 different types: 2 alpha and 1 each of beta, gamma and delta subunits. After acetylcholine binding, the receptor undergoes an extensive conformation change that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane. Defects in this gene are a cause of multiple pterygium syndrome lethal type (MUPSL), congenital myasthenic syndrome slow-channel type (SCCMS), and congenital myasthenic syndrome fast-channel type (FCCMS). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-232531352-GT-G is Pathogenic according to our data. Variant chr2-232531352-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374186.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHRND | NM_000751.3 | c.822delT | p.Ser274ArgfsTer52 | frameshift_variant, splice_region_variant | Exon 8 of 12 | ENST00000258385.8 | NP_000742.1 | |
| CHRND | NM_001256657.2 | c.777delT | p.Ser259ArgfsTer52 | frameshift_variant, splice_region_variant | Exon 7 of 11 | NP_001243586.1 | ||
| CHRND | NM_001311196.2 | c.519delT | p.Ser173ArgfsTer52 | frameshift_variant, splice_region_variant | Exon 8 of 12 | NP_001298125.1 | ||
| CHRND | NM_001311195.2 | c.240delT | p.Gly81ValfsTer51 | frameshift_variant, splice_region_variant | Exon 6 of 10 | NP_001298124.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459716Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726276
GnomAD4 exome
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GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ptosis;C0013404:Dyspnea;C0151786:Muscle weakness;C3808046:Breathing dysregulation Pathogenic:1
Jun 03, 2014
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Computational scores
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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