rs748283

Variant names:

• chr8-27459678-C-A
• rs748283
• NM_000742.4:c.*1951G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000742.4(CHRNA2):​c.*1951G>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 164,308 control chromosomes in the GnomAD database, including 16,132 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 0.43 (14659 hom., cov: 33)
  • Exomes 𝑓: 0.48 (1473 hom.)
• Consequence: CHRNA2 NM_000742.4 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 6 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000742.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA2	NM_000742.4	MANE Select	c.*1951G>T		downstream_gene	N/A	NP_000733.2
	CHRNA2	NM_001282455.2		c.*1951G>T		downstream_gene	N/A	NP_001269384.1
	CHRNA2	NM_001347705.2		c.*1951G>T		downstream_gene	N/A	NP_001334634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.*1951G>T		downstream_gene	N/A	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64807 AN: 151964 Hom.: 14649 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.492

Gnomad OTH AF: 0.481

GnomAD4 exome AF: 0.482 AC: 5898 AN: 12224 Hom.: 1473 AF XY: 0.481 AC XY: 2733 AN XY: 5680

African (AFR) AF: 0.324 AC: 110 AN: 340

American (AMR) AF: 0.465 AC: 118 AN: 254

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 528 AN: 802

East Asian (EAS) AF: 0.432 AC: 1200 AN: 2780

South Asian (SAS) AF: 0.375 AC: 33 AN: 88

European-Finnish (FIN) AF: 0.429 AC: 6 AN: 14

Middle Eastern (MID) AF: 0.585 AC: 48 AN: 82

European-Non Finnish (NFE) AF: 0.492 AC: 3390 AN: 6896

Other (OTH) AF: 0.480 AC: 465 AN: 968

GnomAD4 genome AF: 0.426 AC: 64853 AN: 152084 Hom.: 14659 Cov.: 33 AF XY: 0.427 AC XY: 31757 AN XY: 74342

African (AFR) AF: 0.273 AC: 11329 AN: 41486

American (AMR) AF: 0.453 AC: 6925 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2278 AN: 3472

East Asian (EAS) AF: 0.345 AC: 1783 AN: 5168

South Asian (SAS) AF: 0.419 AC: 2020 AN: 4826

European-Finnish (FIN) AF: 0.523 AC: 5532 AN: 10572

Middle Eastern (MID) AF: 0.589 AC: 172 AN: 292

European-Non Finnish (NFE) AF: 0.492 AC: 33471 AN: 67970

Other (OTH) AF: 0.485 AC: 1023 AN: 2108

Alfa AF: 0.463 Hom.: 2134

Bravo AF: 0.417

Asia WGS AF: 0.384 AC: 1335 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.88
DANN	Benign	0.49
PhyloP100		-1.0
Mutation Taster		=98/2	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs748283; hg19: chr8-27317195;