2-174748734-G-C

Position:

• chr2-174748734-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000079.4(CHRNA1):​c.1088C>G​(p.Thr363Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T363I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19179624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA1	NM_000079.4	c.1088C>G	p.Thr363Arg	missense_variant	8/9	ENST00000348749.9
CHRNA1	NM_001039523.3	c.1163C>G	p.Thr388Arg	missense_variant	9/10
CHRNA1	XM_017003256.2	c.1184C>G	p.Thr395Arg	missense_variant	8/9
CHRNA1	XM_017003257.2	c.1109C>G	p.Thr370Arg	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA1	ENST00000348749.9	c.1088C>G	p.Thr363Arg	missense_variant	8/9	1	NM_000079.4	P1
	ENST00000442996.1	n.321+18910G>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lethal multiple pterygium syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 06, 2023

This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 363 of the CHRNA1 protein (p.Thr363Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHRNA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 568875). 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 not expected to disrupt CHRNA1 protein function. 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	Benign	0.093
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.31	.;T;T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.70	.;N;.;.
MutationTaster	Benign	0.53	D;D;D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N;N;N;.
REVEL	Uncertain	0.29
Sift	Benign	0.38	T;T;T;.
Sift4G	Benign	0.56	T;T;T;.
Polyphen		0.60	.;P;.;.
Vest4		0.27
MutPred		0.37		.;Gain of MoRF binding (P = 0.0218);.;.;
MVP		0.79
MPC		0.62
ClinPred		0.40	T
GERP RS		5.5
Varity_R		0.20
gMVP		0.68

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: rs146771663; hg19: chr2-175613462;