rs2565061

chr8-27467327-G-Achr8-27467327-G-Cchr8-27467327-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000742.4(CHRNA2):c.351C>T(p.Asp117=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,605,228 control chromosomes in the GnomAD database, including 20,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2725 hom., cov: 33)

Exomes 𝑓: 0.14 ( 18004 hom. )

Consequence

CHRNA2
NM_000742.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.09

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 8-27467327-G-A is Benign according to our data. Variant chr8-27467327-G-A is described in ClinVar as [Benign]. Clinvar id is 128738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.09 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNA2	NM_000742.4 linkuse as main transcript	c.351C>T	p.Asp117=	synonymous_variant	5/7	ENST00000407991.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNA2	ENST00000407991.3 linkuse as main transcript	c.351C>T	p.Asp117=	synonymous_variant	5/7	5	NM_000742.4	P2	Q15822-1

Frequencies

GnomAD3 genomes

AF:

0.176

AC:

26727

AN:

152080

Hom.:

2718

Cov.:

show subpopulations

Gnomad AFR

AF:

0.229

Gnomad AMI

AF:

0.124

Gnomad AMR

AF:

0.189

Gnomad ASJ

AF:

0.0548

Gnomad EAS

AF:

0.430

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.164

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.151

GnomAD3 exomes

AF:

0.170

AC:

42777

AN:

251388

Hom.:

4553

AF XY:

0.163

AC XY:

22206

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.231

Gnomad AMR exome

AF:

0.197

Gnomad ASJ exome

AF:

0.0654

Gnomad EAS exome

AF:

0.440

Gnomad SAS exome

AF:

0.131

Gnomad FIN exome

AF:

0.166

Gnomad NFE exome

AF:

0.132

Gnomad OTH exome

AF:

0.143

GnomAD4 exome

AF:

0.145

AC:

210283

AN:

1453030

Hom.:

18004

Cov.:

AF XY:

0.144

AC XY:

103990

AN XY:

723268

show subpopulations

Gnomad4 AFR exome

AF:

0.231

Gnomad4 AMR exome

AF:

0.195

Gnomad4 ASJ exome

AF:

0.0652

Gnomad4 EAS exome

AF:

0.434

Gnomad4 SAS exome

AF:

0.130

Gnomad4 FIN exome

AF:

0.164

Gnomad4 NFE exome

AF:

0.132

Gnomad4 OTH exome

AF:

0.146

GnomAD4 genome

AF:

0.176

AC:

26764

AN:

152198

Hom.:

2725

Cov.:

AF XY:

0.179

AC XY:

13282

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.229

Gnomad4 AMR

AF:

0.189

Gnomad4 ASJ

AF:

0.0548

Gnomad4 EAS

AF:

0.430

Gnomad4 SAS

AF:

0.151

Gnomad4 FIN

AF:

0.164

Gnomad4 NFE

AF:

0.133

Gnomad4 OTH

AF:

0.150

Alfa

AF:

0.143

Hom.:

2628

Bravo

AF:

0.180

Asia WGS

AF:

0.271

AC:

943

AN:

3478

EpiCase

AF:

0.125

EpiControl

AF:

0.122

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 22, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

-0.51

Cadd

Benign

6.3

Dann

Benign

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over