rs2741339

Variant names:

• chr8-27477452-A-G
• rs2741339
• NM_000742.4:c.-137+1372T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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]

CHRNA2 Gene-Disease associations (from GenCC):

• autosomal dominant nocturnal frontal lobe epilepsy 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
• autosomal dominant nocturnal frontal lobe epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sleep-related hypermotor epilepsy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• benign familial infantile epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.-137+1372T>C		intron_variant	Intron 1 of 6	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.-137+1372T>C		intron_variant	Intron 1 of 6	5	NM_000742.4	ENSP00000385026.1

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

African (AFR) AF: 0.701 AC: 29033 AN: 41446

American (AMR) AF: 0.320 AC: 4896 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 1330 AN: 3470

East Asian (EAS) AF: 0.240 AC: 1240 AN: 5170

South Asian (SAS) AF: 0.244 AC: 1172 AN: 4812

European-Finnish (FIN) AF: 0.367 AC: 3875 AN: 10568

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18282 AN: 67954

Other (OTH) AF: 0.363 AC: 765 AN: 2106

Alfa AF: 0.311 Hom.: 16123

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
PhyloP100		0.055
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2741339; hg19: chr8-27334969;