rs2741339

Positions:

• chr8-27477452-A-G

Variant summary

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

The NM_000742.4(CHRNA2):​c.-137+1372T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 152,010 control chromosomes in the GnomAD database, including 14,973 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 0.40 (14973 hom., cov: 31)
• Consequence: CHRNA2 NM_000742.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.-137+1372T>C		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+1372T>C		intron_variant		5	NM_000742.4	ENSP00000385026	P2

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60826 AN: 151892 Hom.: 14936 Cov.: 31

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.383

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.367

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

GnomAD4 genome AF: 0.401 AC: 60916 AN: 152010 Hom.: 14973 Cov.: 31 AF XY: 0.399 AC XY: 29608 AN XY: 74290

Gnomad4 AFR AF: 0.701

Gnomad4 AMR AF: 0.320

Gnomad4 ASJ AF: 0.383

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.367

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.363

Alfa AF: 0.297 Hom.: 10308

Bravo AF: 0.411

Asia WGS AF: 0.272 AC: 949 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.3
DANN	Benign	0.80

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: rs2741339; hg19: chr8-27334969;