8-27479461-G-A

Variant names:

• chr8-27479461-G-A
• rs2565059
• ENST00000524096.5:c.-137+308C>T

Variant summary

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

The ENST00000524096.5(CHRNA2):​c.-137+308C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 151,996 control chromosomes in the GnomAD database, including 3,399 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 0.21 (3399 hom., cov: 32)
• Consequence: CHRNA2 ENST00000524096.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28
• Publications: 17 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000524096.5. 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.-774C>T		upstream_gene	N/A	NP_000733.2
	CHRNA2	NM_001282455.2		c.-774C>T		upstream_gene	N/A	NP_001269384.1
	CHRNA2	NM_001347705.2		c.-1201C>T		upstream_gene	N/A	NP_001334634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA2	ENST00000524096.5	TSL:4	c.-137+308C>T		intron	N/A	ENSP00000430422.1
	CHRNA2	ENST00000520208.1	TSL:4	c.-433+308C>T		intron	N/A	ENSP00000430994.1
	CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.-774C>T		upstream_gene	N/A	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31127 AN: 151878 Hom.: 3395 Cov.: 32

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.0984

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.178

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

GnomAD4 genome AF: 0.205 AC: 31167 AN: 151996 Hom.: 3399 Cov.: 32 AF XY: 0.207 AC XY: 15398 AN XY: 74270

African (AFR) AF: 0.206 AC: 8547 AN: 41446

American (AMR) AF: 0.207 AC: 3169 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3464

East Asian (EAS) AF: 0.103 AC: 530 AN: 5148

South Asian (SAS) AF: 0.0983 AC: 473 AN: 4814

European-Finnish (FIN) AF: 0.333 AC: 3519 AN: 10568

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13729 AN: 67956

Other (OTH) AF: 0.176 AC: 372 AN: 2110

Alfa AF: 0.198 Hom.: 5212

Bravo AF: 0.198

Asia WGS AF: 0.102 AC: 355 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.80
PhyloP100		1.3
PromoterAI		0.0084	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2565059; hg19: chr8-27336978;