rs199470444

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_000079.4(CHRNA1):c.280G>T(p.Gly94Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

CHRNA1
NM_000079.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 7.84

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 links:

ENSG00000236449 (HGNC:):

ENSG00000236449 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 2-174757630-C-A is Pathogenic according to our data. Variant chr2-174757630-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 565596.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA1	NM_000079.4 linkuse as main transcript	c.280G>T	p.Gly94Cys	missense_variant	4/9	ENST00000348749.9	NP_000070.1	P02708-2Q53SH4
CHRNA1	NM_001039523.3 linkuse as main transcript	c.355G>T	p.Gly119Cys	missense_variant	5/10		NP_001034612.1	P02708-1Q53SH4
CHRNA1	XM_017003256.2 linkuse as main transcript	c.376G>T	p.Gly126Cys	missense_variant	4/9		XP_016858745.1
CHRNA1	XM_017003257.2 linkuse as main transcript	c.301G>T	p.Gly101Cys	missense_variant	3/8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9 linkuse as main transcript	c.280G>T	p.Gly94Cys	missense_variant	4/9	1	NM_000079.4	ENSP00000261008.5		P02708-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

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:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251418

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000513

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74264

show subpopulations

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:

0.0000945

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000288

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2024	Published functional studies demonstrate a damaging effect as in-vitro analysis have shown that the G94C variant leads to significantly reduced surface expression of the protein in AChR cultured cells (PMID: 22728938); This variant is associated with the following publications: (PMID: 14719537, 23679851, 25305004, 25159927, 22728938) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 09, 2019	- -

Lethal multiple pterygium syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2023

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 94 of the CHRNA1 protein (p.Gly94Cys). This variant is present in population databases (rs199470444, gnomAD 0.006%). This missense change has been observed in individual(s) with congenital myasthenic syndrome in the compound heterozygous state (PMID: 22728938). This variant is also known as G74C. ClinVar contains an entry for this variant (Variation ID: 565596). 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 expected to disrupt CHRNA1 protein function. Experimental studies have shown that this missense change affects CHRNA1 function (PMID: 22728938). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D;D;T;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.96

D;D;D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Pathogenic

3.9

.;H;.;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.2

D;D;D;.;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;.;D

Polyphen

0.99, 0.99

.;D;.;.;D

Vest4

0.98

MutPred

0.86

.;Loss of disorder (P = 0.0157);.;.;.;

MVP

0.93

MPC

0.90

ClinPred

1.0

GERP RS

5.9

Varity_R

0.96

gMVP

0.75

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over