NM_000751.3:c.1237C>A

Variant names:

• chr2-232534120-C-A
• rs1242056715
• NM_000751.3:c.1237C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000751.3(CHRND):​c.1237C>A​(p.Arg413Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,750 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R413C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55
• Publications: 1 publications found

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]

CHRND Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 3A

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• congenital myasthenic syndrome 3B

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp
• congenital myasthenic syndrome 3C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRND	NM_000751.3	c.1237C>A	p.Arg413Ser	missense_variant	Exon 10 of 12	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.1192C>A	p.Arg398Ser	missense_variant	Exon 9 of 11		NP_001243586.1
CHRND	NM_001311196.2	c.934C>A	p.Arg312Ser	missense_variant	Exon 10 of 12		NP_001298125.1
CHRND	NM_001311195.2	c.655C>A	p.Arg219Ser	missense_variant	Exon 8 of 10		NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.1237C>A	p.Arg413Ser	missense_variant	Exon 10 of 12	1	NM_000751.3	ENSP00000258385.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461750 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lethal multiple pterygium syndrome Uncertain:1

Oct 02, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces arginine with serine at codon 413 of the CHRND protein (p.Arg413Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHRND-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Benign	1.6	.;L
PhyloP100		4.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.57	T;T
Sift4G	Benign	0.48	T;T
Polyphen		1.0	.;D
Vest4		0.72
MutPred		0.47		.;Gain of phosphorylation at R413 (P = 0.0211);
MVP		0.97
MPC		0.93
ClinPred		0.90	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.76
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1242056715; hg19: chr2-233398830;