rs1346726

Positions:

• chr8-27477702-A-C

Variant summary

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

The NM_000742.4(CHRNA2):​c.-137+1122T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 152,152 control chromosomes in the GnomAD database, including 1,910 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 0.10 (1910 hom., cov: 32)
• Consequence: CHRNA2 NM_000742.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131

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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.-137+1122T>G		intron_variant		ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.-137+1122T>G		intron_variant		5	NM_000742.4	ENSP00000385026	P2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15369 AN: 152034 Hom.: 1902 Cov.: 32

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0478

Gnomad ASJ AF: 0.0841

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0895

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.101 AC: 15420 AN: 152152 Hom.: 1910 Cov.: 32 AF XY: 0.0973 AC XY: 7238 AN XY: 74406

Gnomad4 AFR AF: 0.296

Gnomad4 AMR AF: 0.0478

Gnomad4 ASJ AF: 0.0841

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0215

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.0254

Gnomad4 OTH AF: 0.0890

Alfa AF: 0.0604 Hom.: 301

Bravo AF: 0.114

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.9
DANN	Benign	0.76

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: rs1346726; hg19: chr8-27335219;