rs150208750

chr2-232528561-C-Achr2-232528561-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000751.3(CHRND):c.414C>A(p.Phe138Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F138F) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.76

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 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000751.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06408864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRND	NM_000751.3	c.414C>A	p.Phe138Leu	missense_variant	5/12	ENST00000258385.8
CHRND	NM_001311195.2	c.143C>A	p.Ser48Ter	stop_gained	5/10
CHRND	NM_001256657.2	c.369C>A	p.Phe123Leu	missense_variant	4/11
CHRND	NM_001311196.2	c.111C>A	p.Phe37Leu	missense_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRND	ENST00000258385.8	c.414C>A	p.Phe138Leu	missense_variant	5/12	1	NM_000751.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32

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

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74304

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.0010
Dann	Benign	0.85
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.41	T;T;T
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	A;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.64	T;T;T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.28, 0.28
MutPred		0.41		.;.;Gain of relative solvent accessibility (P = 0.1259);
MVP		0.23
MPC		0.28
ClinPred		0.061	T
GERP RS		-7.8
Varity_R		0.054
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150208750; hg19: chr2-233393271; COSMIC: COSV51319199; COSMIC: COSV51319199;