chr2-174754242-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 4.72

Publications

4 publications found

Variant links:

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]

CHRNA1 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 1A
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
lethal multiple pterygium syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
myasthenic syndrome, congenital, 1B, fast-channel
Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CHRNA1 links:

ENSG00000236449 (HGNC:):

ENSG00000236449 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.72157 (below the threshold of 3.09). Trascript score misZ: 1.6771 (below the threshold of 3.09). GenCC associations: The gene is linked to lethal multiple pterygium syndrome, congenital myasthenic syndrome 1A, myasthenic syndrome, congenital, 1B, fast-channel, postsynaptic congenital myasthenic syndrome.

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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 18379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA1	NM_000079.4 link	c.517G>A	p.Gly173Ser	missense_variant	Exon 5 of 9	ENST00000348749.9	NP_000070.1	P02708-2Q53SH4
CHRNA1	NM_001039523.3 link	c.592G>A	p.Gly198Ser	missense_variant	Exon 6 of 10		NP_001034612.1	P02708-1Q53SH4
CHRNA1	XM_017003256.2 link	c.613G>A	p.Gly205Ser	missense_variant	Exon 5 of 9		XP_016858745.1
CHRNA1	XM_017003257.2 link	c.538G>A	p.Gly180Ser	missense_variant	Exon 4 of 8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9 link	c.517G>A	p.Gly173Ser	missense_variant	Exon 5 of 9	1	NM_000079.4	ENSP00000261008.5		P02708-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Sep 06, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 21, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Congenital myasthenic syndrome 1A

Pathogenic:2

May 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 22, 2022

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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;C2931107:Congenital myasthenic syndrome 1A;C4225405:Myasthenic syndrome, congenital, 1B, fast-channel

Pathogenic:1

May 11, 2023

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4,PM2,PP3? -

Lethal multiple pterygium syndrome

Pathogenic:1

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant slow-channel congenital myasthenic syndrome (PMID: 7619526, 9158151, 29054425; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as 457G>A (G153S) or c.592G>A (p.Gly198Ser). ClinVar contains an entry for this variant (Variation ID: 18379). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CHRNA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CHRNA1 function (PMID: 7619526, 9158151). For these reasons, this variant has been classified as Pathogenic. -

Congenital myasthenic syndrome 1A;C4225405:Myasthenic syndrome, congenital, 1B, fast-channel

Pathogenic:1

Mar 02, 2022

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1 PM2 PP3 PP5 -

Congenital myopathy

Pathogenic:1

Mar 01, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

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

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

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

LIST_S2

Uncertain

0.88

D;D;D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D

MetaSVM

Uncertain

0.051

MutationAssessor

Uncertain

2.4

.;M;.;.;.;.

PhyloP100

4.7

PrimateAI

Uncertain

0.68

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

GERP RS

5.8

Varity_R

0.66

gMVP

0.78

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over