rs144063384

Positions:

• chr2-232530016-C-G
• chr2-232530016-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000751.3(CHRND):​c.697C>G​(p.Arg233Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.135

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a topological_domain Extracellular (size 223) in uniprot entity ACHD_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_000751.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRND	NM_000751.3	c.697C>G	p.Arg233Gly	missense_variant	7/12	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.652C>G	p.Arg218Gly	missense_variant	6/11		NP_001243586.1
CHRND	NM_001311196.2	c.394C>G	p.Arg132Gly	missense_variant	7/12		NP_001298125.1
CHRND	NM_001311195.2	c.239-1336C>G		intron_variant			NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.697C>G	p.Arg233Gly	missense_variant	7/12	1	NM_000751.3	ENSP00000258385	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.8	.;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.045	D;D
Sift4G	Benign	0.22	T;T
Polyphen		0.22	.;B
Vest4		0.55
MutPred		0.80		.;Loss of catalytic residue at R233 (P = 0.0469);
MVP		0.85
MPC		0.31
ClinPred		0.33	T
GERP RS		4.3
Varity_R		0.31
gMVP		0.66

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-233394726;