rs1057518958

chr2-232531352-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000751.3(CHRND):c.822del(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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

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/exons	MANE	UniProt
CHRND	NM_000751.3	c.822del	p.Ser274ArgfsTer52	frameshift_variant, splice_region_variant	8/12	ENST00000258385.8
CHRND	NM_001256657.2	c.777del	p.Ser259ArgfsTer52	frameshift_variant, splice_region_variant	7/11
CHRND	NM_001311196.2	c.519del	p.Ser173ArgfsTer52	frameshift_variant, splice_region_variant	8/12
CHRND	NM_001311195.2	c.240del	p.Gly81ValfsTer51	frameshift_variant, splice_region_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRND	ENST00000258385.8	c.822del	p.Ser274ArgfsTer52	frameshift_variant, splice_region_variant	8/12	1	NM_000751.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459716 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726276

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ptosis;C0013404:Dyspnea;C0151786:Muscle weakness;C3808046:Breathing dysregulation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jun 03, 2014

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

Other links and lift over

dbSNP: rs1057518958; hg19: chr2-233396062;