8-27470504-A-G

Variant names:

• chr8-27470504-A-G
• rs2565065
• NM_000742.4:c.73+482T>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.73+482T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 152,250 control chromosomes in the GnomAD database, including 47,887 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 0.79 (47887 hom., cov: 33)
• Consequence: CHRNA2 NM_000742.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00500
• Publications: 20 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.933 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.73+482T>C		intron	N/A	NP_000733.2
	CHRNA2	NM_001282455.2		c.73+482T>C		intron	N/A	NP_001269384.1
	CHRNA2	NM_001347705.2		c.-355+482T>C		intron	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.73+482T>C		intron	N/A	ENSP00000385026.1
	CHRNA2	ENST00000523695.5	TSL:1	n.73+482T>C		intron	N/A	ENSP00000430612.1
	CHRNA2	ENST00000240132.7	TSL:2	c.73+482T>C		intron	N/A	ENSP00000240132.2

Frequencies

GnomAD3 genomes AF: 0.786 AC: 119545 AN: 152132 Hom.: 47827 Cov.: 33

Gnomad AFR AF: 0.941

Gnomad AMI AF: 0.597

Gnomad AMR AF: 0.735

Gnomad ASJ AF: 0.781

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.713

Gnomad OTH AF: 0.784

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

GnomAD4 genome AF: 0.786 AC: 119655 AN: 152250 Hom.: 47887 Cov.: 33 AF XY: 0.787 AC XY: 58561 AN XY: 74432

African (AFR) AF: 0.941 AC: 39136 AN: 41576

American (AMR) AF: 0.734 AC: 11228 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.781 AC: 2710 AN: 3470

East Asian (EAS) AF: 0.813 AC: 4209 AN: 5178

South Asian (SAS) AF: 0.614 AC: 2966 AN: 4830

European-Finnish (FIN) AF: 0.802 AC: 8501 AN: 10596

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.713 AC: 48477 AN: 67990

Other (OTH) AF: 0.786 AC: 1661 AN: 2114

Alfa AF: 0.727 Hom.: 94409

Bravo AF: 0.790

Asia WGS AF: 0.701 AC: 2440 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	4.0
DANN	Benign	0.36
PhyloP100		0.0050
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: rs2565065; hg19: chr8-27328021;