rs56298562

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000742.4(CHRNA2):c.1324C>T(p.Leu442Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,608,776 control chromosomes in the GnomAD database, including 678 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 46 hom., cov: 33)

Exomes 𝑓: 0.026 ( 632 hom. )

Consequence

CHRNA2
NM_000742.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.05

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 8-27463119-G-A is Benign according to our data. Variant chr8-27463119-G-A is described in ClinVar as Benign. ClinVar VariationId is 128737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0178 (2710/152350) while in subpopulation SAS AF = 0.03 (145/4830). AF 95% confidence interval is 0.026. There are 46 homozygotes in GnomAd4. There are 1377 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2710 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA2	NM_000742.4 link	c.1324C>T	p.Leu442Leu	synonymous_variant	Exon 6 of 7	ENST00000407991.3	NP_000733.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA2	ENST00000407991.3 link	c.1324C>T	p.Leu442Leu	synonymous_variant	Exon 6 of 7	5	NM_000742.4	ENSP00000385026.1

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2713

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00374

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0302

Gnomad FIN

AF:

0.0370

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0244

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0224

AC:

5608

AN:

250796

AF XY:

0.0245

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00894

Gnomad ASJ exome

AF:

0.0228

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.0352

Gnomad NFE exome

AF:

0.0257

Gnomad OTH exome

AF:

0.0203

GnomAD4 exome

AF:

0.0261

AC:

37969

AN:

1456426

Hom.:

632

Cov.:

AF XY:

0.0265

AC XY:

19152

AN XY:

723252

show subpopulations

African (AFR)

AF:

0.00404

AC:

135

AN:

33380

American (AMR)

AF:

0.00903

AC:

403

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

578

AN:

26076

East Asian (EAS)

AF:

0.000911

AC:

AN:

39524

South Asian (SAS)

AF:

0.0398

AC:

3429

AN:

86158

European-Finnish (FIN)

AF:

0.0354

AC:

1890

AN:

53322

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0271

AC:

30050

AN:

1107556

Other (OTH)

AF:

0.0226

AC:

1358

AN:

60026

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

2488

4976

7463

9951

12439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1146

2292

3438

4584

5730

<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:

0.0178

AC:

2710

AN:

152350

Hom.:

Cov.:

AF XY:

0.0185

AC XY:

1377

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.00373

AC:

155

AN:

41594

American (AMR)

AF:

0.0144

AC:

220

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0300

AC:

145

AN:

4830

European-Finnish (FIN)

AF:

0.0370

AC:

393

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0244

AC:

1657

AN:

68028

Other (OTH)

AF:

0.0175

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

138

276

413

551

689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0220

Hom.:

Bravo

AF:

0.0152

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0238

EpiControl

AF:

0.0249

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 16, 2012

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. -

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. -

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

Apr 15, 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

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.76

(source)

DANN

Benign

0.56

PhyloP100

3.1

Mutation Taster

=99/1

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