rs114294066

Variant names:

• chr8-27463530-G-A
• rs114294066
• NM_000742.4:c.913C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000742.4(CHRNA2):​c.913C>T​(p.Leu305Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00229 in 1,614,230 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L305L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (42 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (39 hom.)
• Consequence: CHRNA2 NM_000742.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.97
• Publications: 5 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
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-27463530-G-A is Benign according to our data. Variant chr8-27463530-G-A is described in ClinVar as Benign. ClinVar VariationId is 128742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1829/152340) while in subpopulation AFR AF = 0.0417 (1735/41574). AF 95% confidence interval is 0.0401. There are 42 homozygotes in GnomAd4. There are 881 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1829 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA2	NM_000742.4	MANE Select	c.913C>T	p.Leu305Leu	synonymous	Exon 6 of 7	NP_000733.2	Q15822-1
	CHRNA2	NM_001282455.2		c.868C>T	p.Leu290Leu	synonymous	Exon 6 of 7	NP_001269384.1	Q15822-2
	CHRNA2	NM_001347705.2		c.436C>T	p.Leu146Leu	synonymous	Exon 6 of 7	NP_001334634.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.913C>T	p.Leu305Leu	synonymous	Exon 6 of 7	ENSP00000385026.1	Q15822-1
	CHRNA2	ENST00000523695.5	TSL:1	n.*315C>T		non_coding_transcript_exon	Exon 6 of 7	ENSP00000430612.1	E5RJ54
	CHRNA2	ENST00000523695.5	TSL:1	n.*315C>T		3_prime_UTR	Exon 6 of 7	ENSP00000430612.1	E5RJ54

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1819 AN: 152222 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.0416

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00326 AC: 820 AN: 251448 AF XY: 0.00249

Gnomad AFR exome AF: 0.0450

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00128 AC: 1864 AN: 1461890 Hom.: 39 Cov.: 33 AF XY: 0.00108 AC XY: 786 AN XY: 727244

African (AFR) AF: 0.0467 AC: 1564 AN: 33480

American (AMR) AF: 0.00201 AC: 90 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1112012

Other (OTH) AF: 0.00278 AC: 168 AN: 60396

GnomAD4 genome AF: 0.0120 AC: 1829 AN: 152340 Hom.: 42 Cov.: 33 AF XY: 0.0118 AC XY: 881 AN XY: 74488

African (AFR) AF: 0.0417 AC: 1735 AN: 41574

American (AMR) AF: 0.00438 AC: 67 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68032

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00790 Hom.: 20

Bravo AF: 0.0142

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy (1)
-	-	1	Autosomal dominant nocturnal frontal lobe epilepsy 4 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.90
PhyloP100		4.0
Mutation Taster		=97/3	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: rs114294066; hg19: chr8-27321047;