2-174757591-G-T

Variant names:

• chr2-174757591-G-T
• rs140268343
• NM_000079.4:c.319C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000079.4(CHRNA1):​c.319C>A​(p.Arg107Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10

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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.319C>A	p.Arg107Ser	missense_variant	Exon 4 of 9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.394C>A	p.Arg132Ser	missense_variant	Exon 5 of 10		NP_001034612.1
CHRNA1	XM_017003256.2	c.415C>A	p.Arg139Ser	missense_variant	Exon 4 of 9		XP_016858745.1
CHRNA1	XM_017003257.2	c.340C>A	p.Arg114Ser	missense_variant	Exon 3 of 8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.319C>A	p.Arg107Ser	missense_variant	Exon 4 of 9	1	NM_000079.4	ENSP00000261008.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 24, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	.;T;T;T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.65	D;D;D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.6	.;M;.;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.3	N;N;N;.;N
REVEL	Uncertain	0.42
Sift	Benign	0.14	T;T;T;.;T
Sift4G	Benign	0.21	T;T;T;.;T
Polyphen		0.0010, 0.044	.;B;.;.;B
Vest4		0.74
MutPred		0.61		.;Gain of ubiquitination at K129 (P = 0.0849);.;.;.;
MVP		0.72
MPC		0.29
ClinPred		0.76	D
GERP RS		6.1
Varity_R		0.71
gMVP		0.73

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: rs140268343; hg19: chr2-175622319;