2-232535288-C-A

Variant names:

• chr2-232535288-C-A
• rs114463490
• NM_000751.3:c.1530C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000751.3(CHRND):​c.1530C>A​(p.Asn510Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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: 33)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.24

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041630805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRND	NM_000751.3	c.1530C>A	p.Asn510Lys	missense_variant	Exon 12 of 12	ENST00000258385.8	NP_000742.1
CHRND	NM_001256657.2	c.1485C>A	p.Asn495Lys	missense_variant	Exon 11 of 11		NP_001243586.1
CHRND	NM_001311196.2	c.1227C>A	p.Asn409Lys	missense_variant	Exon 12 of 12		NP_001298125.1
CHRND	NM_001311195.2	c.948C>A	p.Asn316Lys	missense_variant	Exon 10 of 10		NP_001298124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRND	ENST00000258385.8	c.1530C>A	p.Asn510Lys	missense_variant	Exon 12 of 12	1	NM_000751.3	ENSP00000258385.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.0010
DANN	Benign	0.66
DEOGEN2	Benign	0.062	.;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.46	.;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.21
Sift	Benign	0.93	T;T
Sift4G	Benign	0.96	T;T
Polyphen		0.013	.;B
Vest4		0.057
MutPred		0.30		.;Gain of ubiquitination at N510 (P = 0.006);
MVP		0.38
MPC		0.28
ClinPred		0.13	T
GERP RS		-10
Varity_R		0.043
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs114463490; hg19: chr2-233399998;