rs2280376

Positions:

• chr8-27460245-G-A
• chr8-27460245-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000742.4(CHRNA2):​c.*1384C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 152,108 control chromosomes in the GnomAD database, including 4,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4639 hom., cov: 31)
  • Exomes 𝑓: 0.27 (4 hom.)
• Consequence: CHRNA2 NM_000742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.124

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 8-27460245-G-A is Benign according to our data. Variant chr8-27460245-G-A is described in ClinVar as [Benign]. Clinvar id is 362671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.*1384C>T		3_prime_UTR_variant	7/7	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3	c.*1384C>T		3_prime_UTR_variant	7/7	5	NM_000742.4	ENSP00000385026	P2

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35662 AN: 151906 Hom.: 4632 Cov.: 31

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.274 AC: 23 AN: 84 Hom.: 4 Cov.: 0 AF XY: 0.231 AC XY: 12 AN XY: 52

Gnomad4 AFR exome AF: 0.250

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.265

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.235 AC: 35698 AN: 152024 Hom.: 4639 Cov.: 31 AF XY: 0.236 AC XY: 17548 AN XY: 74326

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.306

Gnomad4 ASJ AF: 0.374

Gnomad4 EAS AF: 0.229

Gnomad4 SAS AF: 0.254

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.264

Alfa AF: 0.268 Hom.: 5579

Bravo AF: 0.231

Asia WGS AF: 0.218 AC: 759 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Autosomal dominant nocturnal frontal lobe epilepsy 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.2
DANN	Benign	0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs2280376; hg19: chr8-27317762;