rs1424077317

Positions:

• chr2-174754335-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000079.4(CHRNA1):​c.424G>A​(p.Ala142Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 8 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, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.424G>A	p.Ala142Thr	missense_variant	5/9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.499G>A	p.Ala167Thr	missense_variant	6/10		NP_001034612.1
CHRNA1	XM_017003256.2	c.520G>A	p.Ala174Thr	missense_variant	5/9		XP_016858745.1
CHRNA1	XM_017003257.2	c.445G>A	p.Ala149Thr	missense_variant	4/8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.424G>A	p.Ala142Thr	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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myasthenic syndrome, slow-channel congenital Uncertain:1

Uncertain significance, criteria provided, single submitter

research

TIDEX, University of British Columbia

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	.;D;T;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.1	.;M;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	D;D;D;.;D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Uncertain	0.010	D;D;D;.;T
Polyphen		1.0	.;D;.;.;D
Vest4		0.85
MutPred		0.88		.;Loss of ubiquitination at K170 (P = 0.1343);.;.;.;
MVP		0.89
MPC		0.89
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.82

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: rs1424077317; hg19: chr2-175619063;