Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000742.4(CHRNA2):c.351C>T(p.Asp117Asp) 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:8

Conservation

PhyloP100: 3.09

Publications

20 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=-0.51).

BP6

Variant 8-27467327-G-A is Benign according to our data. Variant chr8-27467327-G-A is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000742.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA2	NM_000742.4	MANE Select	c.351C>T	p.Asp117Asp	synonymous	Exon 5 of 7	NP_000733.2
CHRNA2	NM_001282455.2		c.306C>T	p.Asp102Asp	synonymous	Exon 5 of 7	NP_001269384.1
CHRNA2	NM_001347705.2		c.-122C>T		5_prime_UTR	Exon 5 of 7	NP_001334634.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.351C>T	p.Asp117Asp	synonymous	Exon 5 of 7	ENSP00000385026.1
CHRNA2	ENST00000520600.1	TSL:1	n.191C>T		non_coding_transcript_exon	Exon 1 of 2
CHRNA2	ENST00000523695.5	TSL:1	n.351C>T		non_coding_transcript_exon	Exon 5 of 7	ENSP00000430612.1

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

GnomAD2 exomes

AF:

0.170

AC:

42777

AN:

251388

AF XY:

0.163

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 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

African (AFR)

AF:

0.231

AC:

7691

AN:

33258

American (AMR)

AF:

0.195

AC:

8706

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0652

AC:

1702

AN:

26102

East Asian (EAS)

AF:

0.434

AC:

17201

AN:

39594

South Asian (SAS)

AF:

0.130

AC:

11157

AN:

86076

European-Finnish (FIN)

AF:

0.164

AC:

8736

AN:

53398

Middle Eastern (MID)

AF:

0.0703

AC:

405

AN:

5760

European-Non Finnish (NFE)

AF:

0.132

AC:

145939

AN:

1104090

Other (OTH)

AF:

0.146

AC:

8746

AN:

60050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

7387

14773

22160

29546

36933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5420

10840

16260

21680

27100

<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:

0.176

AC:

26764

AN:

152198

Hom.:

2725

Cov.:

AF XY:

0.179

AC XY:

13282

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.229

AC:

9519

AN:

41530

American (AMR)

AF:

0.189

AC:

2883

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0548

AC:

190

AN:

3468

East Asian (EAS)

AF:

0.430

AC:

2216

AN:

5148

South Asian (SAS)

AF:

0.151

AC:

728

AN:

4822

European-Finnish (FIN)

AF:

0.164

AC:

1742

AN:

10606

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.133

AC:

9036

AN:

68018

Other (OTH)

AF:

0.150

AC:

316

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1118

2237

3355

4474

5592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

288

576

864

1152

1440

<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:

0.147

Hom.:

5773

Bravo

AF:

0.180

Asia WGS

AF:

0.271

AC:

943

AN:

3478

EpiCase

AF:

0.125

EpiControl

AF:

0.122

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Autosomal dominant nocturnal frontal lobe epilepsy (1)

Autosomal dominant nocturnal frontal lobe epilepsy 4 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.3

(source)

DANN

Benign

0.49

PhyloP100

3.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs2565061

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over