rs2043063

Variant names:

• chr8-27464917-C-G
• rs2043063
• NM_000742.4:c.450-924G>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.450-924G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.849 in 152,150 control chromosomes in the GnomAD database, including 55,210 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 0.85 (55210 hom., cov: 31)
• Consequence: CHRNA2 NM_000742.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 7 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.87 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.450-924G>C		intron_variant	Intron 5 of 6	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.450-924G>C		intron_variant	Intron 5 of 6	5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.849 AC: 129151 AN: 152032 Hom.: 55170 Cov.: 31

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.935

Gnomad EAS AF: 0.560

Gnomad SAS AF: 0.849

Gnomad FIN AF: 0.828

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.871

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

GnomAD4 genome AF: 0.849 AC: 129243 AN: 152150 Hom.: 55210 Cov.: 31 AF XY: 0.845 AC XY: 62876 AN XY: 74366

African (AFR) AF: 0.877 AC: 36412 AN: 41514

American (AMR) AF: 0.820 AC: 12541 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.935 AC: 3246 AN: 3470

East Asian (EAS) AF: 0.559 AC: 2885 AN: 5158

South Asian (SAS) AF: 0.848 AC: 4085 AN: 4820

European-Finnish (FIN) AF: 0.828 AC: 8765 AN: 10592

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.859 AC: 58395 AN: 67990

Other (OTH) AF: 0.872 AC: 1839 AN: 2110

Alfa AF: 0.861 Hom.: 7022

Bravo AF: 0.851

Asia WGS AF: 0.723 AC: 2514 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.43
DANN	Benign	0.66
PhyloP100		-1.2
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: rs2043063; hg19: chr8-27322434;