rs2292975

chr8-27460908-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000742.4(CHRNA2):c.*721G>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 0.408 in 152,236 control chromosomes in the GnomAD database, including 13,485 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13466 hom., cov: 32)
  • Exomes 𝑓: 0.47 (19 hom.)
• Consequence: CHRNA2 NM_000742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.418

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-27460908-C-A is Benign according to our data. Variant chr8-27460908-C-A is described in ClinVar as [Benign]. Clinvar id is 362683.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA2	NM_000742.4	c.*721G>T		3_prime_UTR_variant	7/7	ENST00000407991.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA2	ENST00000407991.3	c.*721G>T		3_prime_UTR_variant	7/7	5	NM_000742.4	P2
CHRNA2	ENST00000520600.1	n.1136G>T		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61976 AN: 151952 Hom.: 13456 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.458

GnomAD4 exome AF: 0.470 AC: 78 AN: 166 Hom.: 19 Cov.: 0 AF XY: 0.446 AC XY: 50 AN XY: 112

Gnomad4 AMR exome AF: 0.500

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.357

Gnomad4 NFE exome AF: 0.464

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.408 AC: 62023 AN: 152070 Hom.: 13466 Cov.: 32 AF XY: 0.409 AC XY: 30417 AN XY: 74324

Gnomad4 AFR AF: 0.260

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.633

Gnomad4 EAS AF: 0.346

Gnomad4 SAS AF: 0.409

Gnomad4 FIN AF: 0.521

Gnomad4 NFE AF: 0.468

Gnomad4 OTH AF: 0.463

Alfa AF: 0.457 Hom.: 14919

Bravo AF: 0.396

Asia WGS AF: 0.376 AC: 1307 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.87
Cadd	Benign	6.4
Dann	Benign	0.74

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: rs2292975; hg19: chr8-27318425;