8-27461027-A-G

Position:

• chr8-27461027-A-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.*602T>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 0.848 in 154,438 control chromosomes in the GnomAD database, including 55,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55121 hom., cov: 30)
  • Exomes 𝑓: 0.84 (860 hom.)
• Consequence: CHRNA2 NM_000742.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.68

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=-0.97).
• BP6: Variant 8-27461027-A-G is Benign according to our data. Variant chr8-27461027-A-G is described in ClinVar as [Benign]. Clinvar id is 362685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA2	NM_000742.4	c.*602T>C		3_prime_UTR_variant	7/7	ENST00000407991.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA2	ENST00000407991.3	c.*602T>C		3_prime_UTR_variant	7/7	5	NM_000742.4	P2
CHRNA2	ENST00000520600.1	n.1017T>C		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.849 AC: 128951 AN: 151930 Hom.: 55092 Cov.: 30

Gnomad AFR AF: 0.870

Gnomad AMI AF: 0.911

Gnomad AMR AF: 0.818

Gnomad ASJ AF: 0.936

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.847

Gnomad FIN AF: 0.837

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.862

Gnomad OTH AF: 0.871

GnomAD4 exome AF: 0.835 AC: 1994 AN: 2388 Hom.: 860 Cov.: 0 AF XY: 0.834 AC XY: 1207 AN XY: 1448

Gnomad4 AFR exome AF: 0.909

Gnomad4 AMR exome AF: 0.786

Gnomad4 ASJ exome AF: 0.889

Gnomad4 EAS exome AF: 0.485

Gnomad4 SAS exome AF: 0.860

Gnomad4 FIN exome AF: 0.848

Gnomad4 NFE exome AF: 0.857

Gnomad4 OTH exome AF: 0.794

GnomAD4 genome AF: 0.849 AC: 129031 AN: 152050 Hom.: 55121 Cov.: 30 AF XY: 0.844 AC XY: 62743 AN XY: 74314

Gnomad4 AFR AF: 0.870

Gnomad4 AMR AF: 0.818

Gnomad4 ASJ AF: 0.936

Gnomad4 EAS AF: 0.531

Gnomad4 SAS AF: 0.846

Gnomad4 FIN AF: 0.837

Gnomad4 NFE AF: 0.862

Gnomad4 OTH AF: 0.873

Alfa AF: 0.843 Hom.: 4046

Bravo AF: 0.850

Asia WGS AF: 0.725 AC: 2524 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	0.11
DANN	Benign	0.77

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: rs2292976; hg19: chr8-27318544;