chr8-27477702-A-C

Variant names:

• chr8-27477702-A-C
• rs1346726
• NM_000742.4:c.-137+1122T>G

Variant summary

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

The NM_000742.4(CHRNA2):​c.-137+1122T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 152,152 control chromosomes in the GnomAD database, including 1,910 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 0.10 (1910 hom., cov: 32)
• Consequence: CHRNA2 NM_000742.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131
• Publications: 3 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.292 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.-137+1122T>G		intron	N/A	NP_000733.2
	CHRNA2	NM_001282455.2		c.-137+1122T>G		intron	N/A	NP_001269384.1
	CHRNA2	NM_001347705.2		c.-564+1122T>G		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.-137+1122T>G		intron	N/A	ENSP00000385026.1
	CHRNA2	ENST00000523695.5	TSL:1	n.-137+1122T>G		intron	N/A	ENSP00000430612.1
	CHRNA2	ENST00000240132.7	TSL:2	c.-137+1122T>G		intron	N/A	ENSP00000240132.2

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15369 AN: 152034 Hom.: 1902 Cov.: 32

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0478

Gnomad ASJ AF: 0.0841

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0254

Gnomad OTH AF: 0.0895

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

GnomAD4 genome AF: 0.101 AC: 15420 AN: 152152 Hom.: 1910 Cov.: 32 AF XY: 0.0973 AC XY: 7238 AN XY: 74406

African (AFR) AF: 0.296 AC: 12275 AN: 41438

American (AMR) AF: 0.0478 AC: 731 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0841 AC: 292 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.0215 AC: 104 AN: 4828

European-Finnish (FIN) AF: 0.00368 AC: 39 AN: 10608

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0254 AC: 1726 AN: 68010

Other (OTH) AF: 0.0890 AC: 188 AN: 2112

Alfa AF: 0.104 Hom.: 1261

Bravo AF: 0.114

Asia WGS AF: 0.0290 AC: 100 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.9
DANN	Benign	0.76
PhyloP100		0.13
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: rs1346726; hg19: chr8-27335219;