2-174754376-A-G

Variant names:

• chr2-174754376-A-G
• NM_000079.4:c.383T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000079.4(CHRNA1):​c.383T>C​(p.Val128Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ENSG00000236449 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.41033426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.383T>C	p.Val128Ala	missense_variant	Exon 5 of 9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.458T>C	p.Val153Ala	missense_variant	Exon 6 of 10		NP_001034612.1
CHRNA1	XM_017003256.2	c.479T>C	p.Val160Ala	missense_variant	Exon 5 of 9		XP_016858745.1
CHRNA1	XM_017003257.2	c.404T>C	p.Val135Ala	missense_variant	Exon 4 of 8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.383T>C	p.Val128Ala	missense_variant	Exon 5 of 9	1	NM_000079.4	ENSP00000261008.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Benign	0.87
DEOGEN2	Benign	0.28	.;T;T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.68	T;T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.80	.;N;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	2.1	N;N;N;.;N
REVEL	Uncertain	0.41
Sift	Benign	1.0	T;T;T;.;T
Sift4G	Benign	1.0	T;T;T;.;T
Polyphen		0.053, 0.10	.;B;.;.;B
Vest4		0.42
MutPred		0.76		.;Loss of sheet (P = 0.0817);.;.;.;
MVP		0.70
MPC		0.32
ClinPred		0.55	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-175619104;