rs137852801

Positions:

• chr2-174754242-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000079.4(CHRNA1):​c.517G>A​(p.Gly173Ser) variant causes a missense change. 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: 31)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.72

Genes affected

CHRNA1 (HGNC:1955): (cholinergic receptor nicotinic alpha 1 subunit) The muscle acetylcholine receptor consiststs of 5 subunits of 4 different types: 2 alpha subunits and 1 each of the beta, gamma, and delta subunits. This gene encodes an alpha subunit that plays a role in acetlycholine binding/channel gating. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2012]

ENSG00000236449 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a topological_domain Extracellular (size 211) in uniprot entity ACHA_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000079.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9
• PP5: Variant 2-174754242-C-T is Pathogenic according to our data. Variant chr2-174754242-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-174754242-C-T is described in Lovd as [Pathogenic]. Variant chr2-174754242-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.517G>A	p.Gly173Ser	missense_variant	5/9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.592G>A	p.Gly198Ser	missense_variant	6/10		NP_001034612.1
CHRNA1	XM_017003256.2	c.613G>A	p.Gly205Ser	missense_variant	5/9		XP_016858745.1
CHRNA1	XM_017003257.2	c.538G>A	p.Gly180Ser	missense_variant	4/8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.517G>A	p.Gly173Ser	missense_variant	5/9	1	NM_000079.4	ENSP00000261008.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2024	Published functional studies demonstrate a damaging effect with increased acetylcholine binding affinity resulting in a gain-of-function synaptic response (PMID: 7619526) in addition to altered channel activity (PMID: 9158151); Not observed in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also denoted as p.G153S and p.G198S due to alternative nomenclature; This variant is associated with the following publications: (PMID: 31965297, 32703467, 7863154, 6287911, 28492532, 9158151, 7619526, 29054425) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 06, 2023	- -

Congenital myasthenic syndrome 1A Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1997	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.59; 3Cnet: 0.79). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic with strong evidence (ClinVar ID: VCV000018379). A different missense change at the same codon (p.Gly173Ala) has been reported to be associated with CHRNA1- related disorder (PMID: 22406191). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Lethal multiple pterygium syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CHRNA1 function (PMID: 7619526, 9158151). 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 CHRNA1 protein function. ClinVar contains an entry for this variant (Variation ID: 18379). This variant is also known as 457G>A (G153S) or c.592G>A (p.Gly198Ser). This missense change has been observed in individual(s) with autosomal dominant slow-channel congenital myasthenic syndrome (PMID: 7619526, 9158151, 29054425; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 173 of the CHRNA1 protein (p.Gly173Ser). -

Congenital myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Mar 01, 2024

PS1+PS2+PS3+PM1+PM2+PP2+PP3+PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;D;T;T;T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D
MetaSVM	Uncertain	0.051	D
MutationAssessor	Uncertain	2.4	.;M;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N;N;N;N;.;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0050	D;D;D;D;.;D
Sift4G	Benign	0.068	T;T;T;T;.;T
Polyphen		0.96, 0.99	.;D;.;.;.;D
Vest4		0.92
MutPred		0.79		.;Gain of catalytic residue at G198 (P = 0.0312);.;.;.;.;
MVP		0.93
MPC		0.52
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.66
gMVP		0.78

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: rs137852801; hg19: chr2-175618970;