8-27462388-C-T

Variant names:

• chr8-27462388-C-T
• rs11778371
• NM_000742.4:c.1464+591G>A

Variant summary

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

The NM_000742.4(CHRNA2):​c.1464+591G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 150,744 control chromosomes in the GnomAD database, including 170 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 0.040 (170 hom., cov: 33)
• Consequence: CHRNA2 NM_000742.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.1464+591G>A		intron_variant	Intron 6 of 6	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.1464+591G>A		intron_variant	Intron 6 of 6	5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 5968 AN: 150624 Hom.: 170 Cov.: 33

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0458

Gnomad AMR AF: 0.0393

Gnomad ASJ AF: 0.0442

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00912

Gnomad FIN AF: 0.0597

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0592

Gnomad OTH AF: 0.0433

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

GnomAD4 genome AF: 0.0396 AC: 5970 AN: 150744 Hom.: 170 Cov.: 33 AF XY: 0.0386 AC XY: 2849 AN XY: 73736

African (AFR) AF: 0.0101 AC: 419 AN: 41314

American (AMR) AF: 0.0392 AC: 595 AN: 15172

Ashkenazi Jewish (ASJ) AF: 0.0442 AC: 153 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 4980

South Asian (SAS) AF: 0.00933 AC: 43 AN: 4610

European-Finnish (FIN) AF: 0.0597 AC: 612 AN: 10244

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0592 AC: 4009 AN: 67672

Other (OTH) AF: 0.0428 AC: 90 AN: 2102

Alfa AF: 0.0528 Hom.: 399

Bravo AF: 0.0378

Asia WGS AF: 0.00462 AC: 16 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	0.82
DANN	Benign	0.68
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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: rs11778371; hg19: chr8-27319905;