rs2472553

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000742.4(CHRNA2):c.65C>T(p.Thr22Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,613,474 control chromosomes in the GnomAD database, including 19,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2187 hom., cov: 32)

Exomes 𝑓: 0.14 ( 17728 hom. )

Consequence

CHRNA2
NM_000742.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.296

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002926439).

BP6

Variant 8-27470994-G-A is Benign according to our data. Variant chr8-27470994-G-A is described in ClinVar as [Benign]. Clinvar id is 128740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNA2	NM_000742.4 linkuse as main transcript	c.65C>T	p.Thr22Ile	missense_variant	2/7	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3 linkuse as main transcript	c.65C>T	p.Thr22Ile	missense_variant	2/7	5	NM_000742.4	ENSP00000385026	P2	Q15822-1

Frequencies

GnomAD3 genomes

AF:

0.158

AC:

24048

AN:

152064

Hom.:

2183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.0846

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.0550

Gnomad EAS

AF:

0.438

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.164

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.133

GnomAD3 exomes

AF:

0.166

AC:

41628

AN:

250562

Hom.:

4435

AF XY:

0.160

AC XY:

21720

AN XY:

135500

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.194

Gnomad ASJ exome

AF:

0.0655

Gnomad EAS exome

AF:

0.450

Gnomad SAS exome

AF:

0.127

Gnomad FIN exome

AF:

0.166

Gnomad NFE exome

AF:

0.131

Gnomad OTH exome

AF:

0.141

GnomAD4 exome

AF:

0.145

AC:

211462

AN:

1461292

Hom.:

17728

Cov.:

AF XY:

0.144

AC XY:

104428

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.170

Gnomad4 AMR exome

AF:

0.191

Gnomad4 ASJ exome

AF:

0.0654

Gnomad4 EAS exome

AF:

0.444

Gnomad4 SAS exome

AF:

0.127

Gnomad4 FIN exome

AF:

0.164

Gnomad4 NFE exome

AF:

0.134

Gnomad4 OTH exome

AF:

0.144

GnomAD4 genome

AF:

0.158

AC:

24080

AN:

152182

Hom.:

2187

Cov.:

AF XY:

0.162

AC XY:

12038

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.170

Gnomad4 AMR

AF:

0.180

Gnomad4 ASJ

AF:

0.0550

Gnomad4 EAS

AF:

0.439

Gnomad4 SAS

AF:

0.149

Gnomad4 FIN

AF:

0.164

Gnomad4 NFE

AF:

0.133

Gnomad4 OTH

AF:

0.132

Alfa

AF:

0.136

Hom.:

4049

Bravo

AF:

0.160

TwinsUK

AF:

0.138

AC:

513

ALSPAC

AF:

0.130

AC:

501

ESP6500AA

AF:

0.184

AC:

810

ESP6500EA

AF:

0.131

AC:

1125

ExAC

AF:

0.165

AC:

19975

Asia WGS

AF:

0.262

AC:

909

AN:

3478

EpiCase

AF:

0.125

EpiControl

AF:

0.121

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 29% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 27. Only high quality variants are reported. -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

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

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

6.2

DANN

Benign

0.061

DEOGEN2

Benign

0.090

T;.;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0096

LIST_S2

Benign

0.41

T;T;T;T;T

MetaRNN

Benign

0.0029

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N;.;.;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

0.23

N;N;N;N;N

REVEL

Benign

0.078

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

0.89

T;T;.;T;.

Polyphen

0.0

B;.;.;.;.

Vest4

0.011

MPC

0.19

ClinPred

0.00054

GERP RS

-2.5

Varity_R

0.028

gMVP

0.28

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

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