2-174748177-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_000079.4(CHRNA1):c.1321G>A(p.Gly441Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CHRNA1
NM_000079.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.91

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.873

PP5

Variant 2-174748177-C-T is Pathogenic according to our data. Variant chr2-174748177-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CHRNA1	NM_000079.4 linkuse as main transcript	c.1321G>A	p.Gly441Arg	missense_variant	9/9	ENST00000348749.9
CHRNA1	NM_001039523.3 linkuse as main transcript	c.1396G>A	p.Gly466Arg	missense_variant	10/10
CHRNA1	XM_017003256.2 linkuse as main transcript	c.1417G>A	p.Gly473Arg	missense_variant	9/9
CHRNA1	XM_017003257.2 linkuse as main transcript	c.1342G>A	p.Gly448Arg	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA1	ENST00000348749.9 linkuse as main transcript	c.1321G>A	p.Gly441Arg	missense_variant	9/9	1	NM_000079.4	P1	P02708-2
	ENST00000442996.1 linkuse as main transcript	n.321+18353C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251230

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000260

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000201

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:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0000967

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 08, 2021	This variant appears to segregate with disease in at least one family (PMID: 27748205). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 24121633). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2021	Published functional studies demonstrate reduced expression as compared to wild-type protein (Rahman et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27748205, 24121633) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 28, 2022	- -

Lethal multiple pterygium syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 06, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 441 of the CHRNA1 protein (p.Gly441Arg). This variant is present in population databases (rs768407867, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive severe congenital myasthenic syndrome (PMID: 24121633, 27748205; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly421Arg and p.Gly466Arg. ClinVar contains an entry for this variant (Variation ID: 449923). 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: 24121633). For these reasons, this variant has been classified as Pathogenic. -

Autism;C0036572:Seizure

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Mar 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.43

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.87

D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-7.1

D;D;D;N;.

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;.

Polyphen

1.0

.;D;.;.;.

Vest4

0.84

MutPred

0.94

.;Gain of helix (P = 0.132);.;.;.;

MVP

0.93

MPC

1.0

ClinPred

0.89

GERP RS

5.2

Varity_R

0.97

gMVP

0.95

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

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