rs143103435

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_000744.7(CHRNA4):c.296G>A(p.Arg99His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,593,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R99C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CHRNA4
NM_000744.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 1.98

Publications

3 publications found

Variant links:

Genes affected

CHRNA4 (HGNC:1958): (cholinergic receptor nicotinic alpha 4 subunit) This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2012]

CHRNA4 Gene-Disease associations (from GenCC):

autosomal dominant nocturnal frontal lobe epilepsy 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
familial sleep-related hypermotor epilepsy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant nocturnal frontal lobe epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CHRNA4 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=0.040449172).

BP6

Variant 20-63356062-C-T is Benign according to our data. Variant chr20-63356062-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205045.

BS2

High AC in GnomAd4 at 28 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000744.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNA4	NM_000744.7	MANE Select	c.296G>A	p.Arg99His	missense	Exon 4 of 6	NP_000735.1	P43681-1
CHRNA4	NM_001256573.2		c.-251G>A		5_prime_UTR	Exon 4 of 6	NP_001243502.1	Q4VAQ3
CHRNA4	NR_046317.2		n.505G>A		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.296G>A	p.Arg99His	missense	Exon 4 of 6	ENSP00000359285.4	P43681-1
CHRNA4	ENST00000467563.3	TSL:1	n.348G>A		non_coding_transcript_exon	Exon 4 of 6
CHRNA4	ENST00000627000.1	TSL:1	n.321G>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000486914.1	A0A0D9SFU6

Frequencies

GnomAD3 genomes

AF:

0.000201

AC:

AN:

139248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000747

Gnomad ASJ

AF:

0.00684

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000613

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000326

AC:

AN:

248256

AF XY:

0.000400

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00642

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000807

Gnomad OTH exome

AF:

0.000987

GnomAD4 exome

AF:

0.000179

AC:

260

AN:

1454016

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

143

AN XY:

723242

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33346

American (AMR)

AF:

0.0000449

AC:

AN:

44502

Ashkenazi Jewish (ASJ)

AF:

0.00699

AC:

181

AN:

25894

East Asian (EAS)

AF:

0.00

AC:

AN:

39286

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51742

Middle Eastern (MID)

AF:

0.000523

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0000370

AC:

AN:

1107448

Other (OTH)

AF:

0.000501

AC:

AN:

59894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000201

AC:

AN:

139248

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

AN XY:

66850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

36564

American (AMR)

AF:

0.0000747

AC:

AN:

13378

Ashkenazi Jewish (ASJ)

AF:

0.00684

AC:

AN:

3364

East Asian (EAS)

AF:

0.00

AC:

AN:

4828

South Asian (SAS)

AF:

0.00

AC:

AN:

4082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8736

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.0000613

AC:

AN:

65228

Other (OTH)

AF:

0.00

AC:

AN:

1896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000432

Hom.:

Bravo

AF:

0.000230

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000257

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autosomal dominant nocturnal frontal lobe epilepsy (1)

Inborn genetic diseases (1)

Autosomal dominant nocturnal frontal lobe epilepsy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Benign

-0.031

Eigen_PC

Benign

0.012

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.040

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.4

PhyloP100

2.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.46

Sift

Uncertain

0.021

Sift4G

Uncertain

0.032

Polyphen

0.17

Vest4

0.46

MVP

0.78

MPC

0.51

ClinPred

0.11

GERP RS

3.2

Varity_R

0.21

gMVP

0.53

Mutation Taster

=67/33

polymorphism

(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

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

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