rs56344740

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000742.4(CHRNA2):c.1434C>A(p.Asp478Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00474 in 1,614,098 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D478N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0049 ( 23 hom. )

Consequence

CHRNA2
NM_000742.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 0.0850

Publications

14 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
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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012082964).

BP6

Variant 8-27463009-G-T is Benign according to our data. Variant chr8-27463009-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136753.

BS2

High AC in GnomAd4 at 485 AD gene.

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	UniProt
CHRNA2	NM_000742.4	MANE Select	c.1434C>A	p.Asp478Glu	missense	Exon 6 of 7	NP_000733.2	Q15822-1
CHRNA2	NM_001282455.2		c.1389C>A	p.Asp463Glu	missense	Exon 6 of 7	NP_001269384.1	Q15822-2
CHRNA2	NM_001347705.2		c.957C>A	p.Asp319Glu	missense	Exon 6 of 7	NP_001334634.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNA2	ENST00000407991.3	TSL:5 MANE Select	c.1434C>A	p.Asp478Glu	missense	Exon 6 of 7	ENSP00000385026.1	Q15822-1
CHRNA2	ENST00000523695.5	TSL:1	n.*836C>A		non_coding_transcript_exon	Exon 6 of 7	ENSP00000430612.1	E5RJ54
CHRNA2	ENST00000523695.5	TSL:1	n.*836C>A		3_prime_UTR	Exon 6 of 7	ENSP00000430612.1	E5RJ54

Frequencies

GnomAD3 genomes

AF:

0.00319

AC:

485

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00569

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00307

AC:

770

AN:

251014

AF XY:

0.00316

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00556

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00491

AC:

7170

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00476

AC XY:

3459

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33480

American (AMR)

AF:

0.00233

AC:

104

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000336

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000338

AC:

AN:

53294

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00606

AC:

6738

AN:

1112006

Other (OTH)

AF:

0.00368

AC:

222

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

446

893

1339

1786

2232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.00318

AC:

485

AN:

152336

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

229

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000938

AC:

AN:

41584

American (AMR)

AF:

0.00340

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00569

AC:

387

AN:

68028

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00429

Hom.:

Bravo

AF:

0.00310

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00337

AC:

409

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00578

EpiControl

AF:

0.00468

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant nocturnal frontal lobe epilepsy 4 (3)

not provided (3)

not specified (2)

Autosomal dominant nocturnal frontal lobe epilepsy (1)

CHRNA2-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

4.2

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.21

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.93

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

M_CAP

Benign

0.018

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.51

PhyloP100

0.085

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.060

REVEL

Benign

0.097

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.24

MutPred

0.40

Gain of phosphorylation at Y475 (P = 0.0745)

MVP

0.48

MPC

0.18

ClinPred

0.012

GERP RS

-6.0

Varity_R

0.11

gMVP

0.47

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over