rs2565055

Positions:

• chr8-27479863-G-T

Variant summary

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

The ENST00000524096.5(CHRNA2):​c.-231C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 151,940 control chromosomes in the GnomAD database, including 5,660 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 0.27 (5654 hom., cov: 31)
  • Exomes 𝑓: 0.27 (6 hom.)
• Consequence: CHRNA2 ENST00000524096.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0660

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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000524096.5	c.-231C>A		5_prime_UTR_variant	1/4	4		ENSP00000430422
CHRNA2	ENST00000520208.1			upstream_gene_variant		4		ENSP00000430994

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40792 AN: 151736 Hom.: 5645 Cov.: 31

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.187

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.261

GnomAD4 exome AF: 0.267 AC: 23 AN: 86 Hom.: 6 Cov.: 0 AF XY: 0.271 AC XY: 13 AN XY: 48

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.750

Gnomad4 FIN exome AF: 0.429

Gnomad4 NFE exome AF: 0.232

Gnomad4 OTH exome AF: 0.100

GnomAD4 genome AF: 0.269 AC: 40840 AN: 151854 Hom.: 5654 Cov.: 31 AF XY: 0.271 AC XY: 20116 AN XY: 74194

Gnomad4 AFR AF: 0.310

Gnomad4 AMR AF: 0.253

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.356

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.258

Alfa AF: 0.248 Hom.: 4823

Bravo AF: 0.264

Asia WGS AF: 0.228 AC: 795 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.7
DANN	Benign	0.79

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2565055; hg19: chr8-27337380;