rs1060499782

chr2-232535129-GGA-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Strong PM2 PP3_Moderate PP5_Moderate

The NM_000751.3(CHRND):c.1374_1375del(p.Lys459ArgfsTer113) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,238 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: CHRND NM_000751.3 frameshift, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.95

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 10 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. Fraction of 0.117 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-232535129-GGA-G is Pathogenic according to our data. Variant chr2-232535129-GGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402225.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.1374_1375del	p.Lys459ArgfsTer113	frameshift_variant, splice_region_variant	12/12	ENST00000258385.8
CHRND	NM_001256657.2	c.1329_1330del	p.Lys444ArgfsTer113	frameshift_variant, splice_region_variant	11/11
CHRND	NM_001311195.2	c.792_793del	p.Lys265ArgfsTer113	frameshift_variant, splice_region_variant	10/10
CHRND	NM_001311196.2	c.1071_1072del	p.Lys358ArgfsTer113	frameshift_variant, splice_region_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRND	ENST00000258385.8	c.1374_1375del	p.Lys459ArgfsTer113	frameshift_variant, splice_region_variant	12/12	1	NM_000751.3	P1
CHRND	ENST00000543200.5	c.1329_1330del	p.Lys444ArgfsTer113	frameshift_variant, splice_region_variant	11/11	2
CHRND	ENST00000441621.6	c.*556_*557del		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	11/11	5
CHRND	ENST00000446616.1	c.*1015_*1016del		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	12/12	3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lethal multiple pterygium syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Mar 24, 2016

The c.1374_1375delGA (p. Lys459Argfs*113) frameshift variant in the CHRND gene has not been previously reported. This variant is predicted to result in the loss of a stop codon or loss of the splice acceptor site in the last exon of this gene, which contains a ligand-gated ion channel domain. Multiple in silico algorithms predict this variant to have a deleterious effect (GERP=5.13, Human Splicing Finder v3.0 predicts creation of a new splice acceptor). This variant is absent from the population databases (Exome Sequencing Project; 1000 Genomes; and ExAC). One family with multiple affected individuals that are compound heterozygous for a nonsense variant (p.Arg464*), which is downstream of this variant and a missense variant (p.Phe74Leu) has been reported (Michalk et al., 2008). Therefore, this collective evidence supports the classification of c.1374_1375delGA (p. Lys459Argfs*113) as a Likely pathogenic variant for Lethal Multiple Pterygium Syndrome. We have confirmed this finding in our laboratory using Sanger sequencing. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 3
DS_AL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060499782; hg19: chr2-233399839;