rs2472553

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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

Publications

44 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant nocturnal frontal lobe epilepsy 4
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Illumina, Labcorp Genetics (formerly Invitae)
autosomal dominant nocturnal frontal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial sleep-related hypermotor epilepsy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
benign familial infantile epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CHRNA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4 link	c.65C>T	p.Thr22Ile	missense_variant	Exon 2 of 7	ENST00000407991.3	NP_000733.2	Q15822-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3 link	c.65C>T	p.Thr22Ile	missense_variant	Exon 2 of 7	5	NM_000742.4	ENSP00000385026.1		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

GnomAD2 exomes

AF:

0.166

AC:

41628

AN:

250562

AF XY:

0.160

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 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

African (AFR)

AF:

0.170

AC:

5676

AN:

33466

American (AMR)

AF:

0.191

AC:

8559

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0654

AC:

1710

AN:

26128

East Asian (EAS)

AF:

0.444

AC:

17610

AN:

39672

South Asian (SAS)

AF:

0.127

AC:

10940

AN:

86242

European-Finnish (FIN)

AF:

0.164

AC:

8757

AN:

53394

Middle Eastern (MID)

AF:

0.0687

AC:

396

AN:

5768

European-Non Finnish (NFE)

AF:

0.134

AC:

149139

AN:

1111560

Other (OTH)

AF:

0.144

AC:

8675

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

9179

18358

27536

36715

45894

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5574

11148

16722

22296

27870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.158

AC:

24080

AN:

152182

Hom.:

2187

Cov.:

AF XY:

0.162

AC XY:

12038

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.170

AC:

7041

AN:

41532

American (AMR)

AF:

0.180

AC:

2746

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0550

AC:

191

AN:

3470

East Asian (EAS)

AF:

0.439

AC:

2264

AN:

5162

South Asian (SAS)

AF:

0.149

AC:

717

AN:

4828

European-Finnish (FIN)

AF:

0.164

AC:

1737

AN:

10584

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.133

AC:

9012

AN:

67998

Other (OTH)

AF:

0.132

AC:

278

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1017

2034

3051

4068

5085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

264

528

792

1056

1320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.141

Hom.:

7838

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

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Jun 25, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 07, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 08, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal dominant nocturnal frontal lobe epilepsy 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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;.;.;.

PhyloP100

0.30

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

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over