chr2-174754376-A-C

Position:

• chr2-174754376-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000079.4(CHRNA1):​c.383T>G​(p.Val128Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

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 Likely_pathogenic. Variant got 6 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, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.383T>G	p.Val128Gly	missense_variant	5/9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.458T>G	p.Val153Gly	missense_variant	6/10		NP_001034612.1
CHRNA1	XM_017003256.2	c.479T>G	p.Val160Gly	missense_variant	5/9		XP_016858745.1
CHRNA1	XM_017003257.2	c.404T>G	p.Val135Gly	missense_variant	4/8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.383T>G	p.Val128Gly	missense_variant	5/9	1	NM_000079.4	ENSP00000261008	P1
	ENST00000442996.1	n.322-18373A>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Feb 05, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 466179). 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 valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 128 of the CHRNA1 protein (p.Val128Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;D;T;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.86	D;T;T;D;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.6	.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.4	N;N;N;.;N
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;.;D
Polyphen		0.78, 0.99	.;P;.;.;D
Vest4		0.58
MutPred		0.80		.;Loss of ubiquitination at K152 (P = 0.0454);.;.;.;
MVP		0.91
MPC		0.71
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553469444; hg19: chr2-175619104;