rs142531974

chr2-232526259-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000751.3(CHRND):c.44C>T(p.Ala15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,612,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A15A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: CHRND NM_000751.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: -0.234

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012229711).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRND	NM_000751.3	c.44C>T	p.Ala15Val	missense_variant	1/12	ENST00000258385.8
CHRND	NM_001256657.2	c.44C>T	p.Ala15Val	missense_variant	1/11
CHRND	NM_001311195.2	c.-228C>T		5_prime_UTR_variant	1/10
CHRND	NM_001311196.2	c.-228C>T		5_prime_UTR_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRND	ENST00000258385.8	c.44C>T	p.Ala15Val	missense_variant	1/12	1	NM_000751.3	P1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000762 AC: 19 AN: 249186 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135002

Gnomad AFR exome AF: 0.000807

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1460726 Hom.: 0 Cov.: 35 AF XY: 0.0000440 AC XY: 32 AN XY: 726582

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74436

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000195 Hom.: 0

Bravo AF: 0.000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 13, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2014	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 02, 2016

- -

Lethal multiple pterygium syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	1.6
Dann	Benign	0.86
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.39	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.68	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.075, 0.080
MVP		0.35
MPC		0.24
ClinPred		0.0010	T
GERP RS		-2.4
Varity_R		0.029
gMVP		0.48

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: rs142531974; hg19: chr2-233390969; COSMIC: COSV51317306; COSMIC: COSV51317306;