2-174748155-C-T

Variant summary

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

The NM_000079.4(CHRNA1):c.1343G>A(p.Gly448Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.84

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA1	NM_000079.4	c.1343G>A	p.Gly448Asp	missense_variant	9/9	ENST00000348749.9
CHRNA1	NM_001039523.3	c.1418G>A	p.Gly473Asp	missense_variant	10/10
CHRNA1	XM_017003256.2	c.1439G>A	p.Gly480Asp	missense_variant	9/9
CHRNA1	XM_017003257.2	c.1364G>A	p.Gly455Asp	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA1	ENST00000348749.9	c.1343G>A	p.Gly448Asp	missense_variant	9/9	1	NM_000079.4	P1
	ENST00000442996.1	n.321+18331C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lethal multiple pterygium syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 08, 2022

This variant has not been reported in the literature in individuals affected with CHRNA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 448 of the CHRNA1 protein (p.Gly448Asp). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Feb 08, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Uncertain	0.064	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.97	N;N;N;N;.
REVEL	Uncertain	0.58
Sift	Benign	0.085	T;T;D;D;.
Sift4G	Benign	0.60	T;T;T;D;.
Polyphen		1.0	.;D;.;.;.
Vest4		0.83
MutPred		0.49		.;Loss of catalytic residue at A472 (P = 0.1478);.;.;.;
MVP		0.83
MPC		0.97
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.46
gMVP		0.80

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: rs1683769492; hg19: chr2-175612883;