8-27461118-C-G

Position:

• chr8-27461118-C-G

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.*511G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.836 in 182,446 control chromosomes in the GnomAD database, including 64,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54132 hom., cov: 32)
  • Exomes 𝑓: 0.81 (10196 hom.)
• Consequence: CHRNA2 NM_000742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.21

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 8-27461118-C-G is Benign according to our data. Variant chr8-27461118-C-G is described in ClinVar as [Benign]. Clinvar id is 362686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA2	NM_000742.4	c.*511G>C		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	c.*511G>C		3_prime_UTR_variant	7/7	5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127779 AN: 152026 Hom.: 54091 Cov.: 32

Gnomad AFR AF: 0.876

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.843

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.850

Gnomad OTH AF: 0.863

GnomAD4 exome AF: 0.811 AC: 24564 AN: 30300 Hom.: 10196 Cov.: 0 AF XY: 0.815 AC XY: 13137 AN XY: 16110

Gnomad4 AFR exome AF: 0.864

Gnomad4 AMR exome AF: 0.817

Gnomad4 ASJ exome AF: 0.907

Gnomad4 EAS exome AF: 0.471

Gnomad4 SAS exome AF: 0.858

Gnomad4 FIN exome AF: 0.794

Gnomad4 NFE exome AF: 0.834

Gnomad4 OTH exome AF: 0.838

GnomAD4 genome AF: 0.840 AC: 127873 AN: 152146 Hom.: 54132 Cov.: 32 AF XY: 0.835 AC XY: 62125 AN XY: 74368

Gnomad4 AFR AF: 0.876

Gnomad4 AMR AF: 0.808

Gnomad4 ASJ AF: 0.929

Gnomad4 EAS AF: 0.523

Gnomad4 SAS AF: 0.841

Gnomad4 FIN AF: 0.802

Gnomad4 NFE AF: 0.850

Gnomad4 OTH AF: 0.865

Alfa AF: 0.809 Hom.: 2484

Bravo AF: 0.843

Asia WGS AF: 0.724 AC: 2519 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	-0.97
CADD	Benign	0.49
DANN	Benign	0.63

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: rs2292977; hg19: chr8-27318635;