rs121909502

Variant names:

• chr2-232531397-C-T
• rs121909502
• NM_000751.3:c.866C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000751.3(CHRND):​c.866C>T​(p.Ser289Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.87
• Publications: 5 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 2-232531397-C-T is Pathogenic according to our data. Variant chr2-232531397-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 18363.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.866C>T	p.Ser289Phe	missense_variant	Exon 8 of 12	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.821C>T	p.Ser274Phe	missense_variant	Exon 7 of 11		NP_001243586.1
CHRND	NM_001311196.2	c.563C>T	p.Ser188Phe	missense_variant	Exon 8 of 12		NP_001298125.1
CHRND	NM_001311195.2	c.284C>T	p.Ser95Phe	missense_variant	Exon 6 of 10		NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.866C>T	p.Ser289Phe	missense_variant	Exon 8 of 12	1	NM_000751.3	ENSP00000258385.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 3A Pathogenic:1

Jan 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lethal multiple pterygium syndrome Pathogenic:1

Mar 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 289 of the CHRND protein (p.Ser289Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 11782989). In at least one individual the variant was observed to be de novo. This variant is also known as S268F. ClinVar contains an entry for this variant (Variation ID: 18363). 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 80%. Experimental studies have shown that this missense change affects CHRND function (PMID: 11782989). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.8	.;M
PhyloP100		7.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.84
MutPred		0.95		.;Gain of catalytic residue at S289 (P = 0.2557);
MVP		1.0
MPC		0.92
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.85
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs121909502; hg19: chr2-233396107;