NM_000742.4:c.*1951G>T

Variant names:

• chr8-27459678-C-A
• rs748283
• NM_000742.4:c.*1951G>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000742.4(CHRNA2):​c.*1951G>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 164,308 control chromosomes in the GnomAD database, including 16,132 homozygotes. 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: 𝑓 0.43 (14659 hom., cov: 33)
  • Exomes 𝑓: 0.48 (1473 hom.)
• Consequence: CHRNA2 NM_000742.4 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02

Genes affected

CHRNA2 (HGNC:1956): (cholinergic receptor nicotinic alpha 2 subunit) Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels formed by a pentameric arrangement of alpha and beta subunits to create distinct muscle and neuronal receptors. Neuronal receptors are found throughout the peripheral and central nervous system where they are involved in fast synaptic transmission. This gene encodes an alpha subunit that is widely expressed in the brain. The proposed structure for nAChR subunits is a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region. Mutations in this gene cause autosomal dominant nocturnal frontal lobe epilepsy type 4. Single nucleotide polymorphisms (SNPs) in this gene have been associated with nicotine dependence. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.*1951G>T		downstream_gene_variant		ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.*1951G>T		downstream_gene_variant		5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64807 AN: 151964 Hom.: 14649 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.481

GnomAD4 exome AF: 0.482 AC: 5898 AN: 12224 Hom.: 1473 AF XY: 0.481 AC XY: 2733 AN XY: 5680

Gnomad4 AFR exome AF: 0.324

Gnomad4 AMR exome AF: 0.465

Gnomad4 ASJ exome AF: 0.658

Gnomad4 EAS exome AF: 0.432

Gnomad4 SAS exome AF: 0.375

Gnomad4 FIN exome AF: 0.429

Gnomad4 NFE exome AF: 0.492

Gnomad4 OTH exome AF: 0.480

GnomAD4 genome AF: 0.426 AC: 64853 AN: 152084 Hom.: 14659 Cov.: 33 AF XY: 0.427 AC XY: 31757 AN XY: 74342

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.453

Gnomad4 ASJ AF: 0.656

Gnomad4 EAS AF: 0.345

Gnomad4 SAS AF: 0.419

Gnomad4 FIN AF: 0.523

Gnomad4 NFE AF: 0.492

Gnomad4 OTH AF: 0.485

Alfa AF: 0.463 Hom.: 2134

Bravo AF: 0.417

Asia WGS AF: 0.384 AC: 1335 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.88
DANN	Benign	0.49

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs748283; hg19: chr8-27317195;