rs2229959

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000744.7(CHRNA4):c.1209G>T(p.Pro403Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.858 in 1,600,374 control chromosomes in the GnomAD database, including 596,316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.76 ( 46728 hom., cov: 33)

Exomes 𝑓: 0.87 ( 549588 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.72

Publications

30 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: Labcorp Genetics (formerly Invitae), G2P
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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 20-63350202-C-A is Benign according to our data. Variant chr20-63350202-C-A is described in ClinVar as Benign. ClinVar VariationId is 93424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.72 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.874 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7 link	c.1209G>T	p.Pro403Pro	synonymous_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1	P43681-1B4DK78Q59FV0
CHRNA4	NM_001256573.2 link	c.681G>T	p.Pro227Pro	synonymous_variant	Exon 5 of 6		NP_001243502.1	P43681Q4VAQ3B4DK78Q59FV0
CHRNA4	NR_046317.2 link	n.1418G>T		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9 link	c.1209G>T	p.Pro403Pro	synonymous_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4		P43681-1

Frequencies

GnomAD3 genomes

AF:

0.763

AC:

116126

AN:

152098

Hom.:

46713

Cov.:

show subpopulations

Gnomad AFR

AF:

0.478

Gnomad AMI

AF:

0.914

Gnomad AMR

AF:

0.855

Gnomad ASJ

AF:

0.837

Gnomad EAS

AF:

0.870

Gnomad SAS

AF:

0.783

Gnomad FIN

AF:

0.894

Gnomad MID

AF:

0.750

Gnomad NFE

AF:

0.880

Gnomad OTH

AF:

0.776

GnomAD2 exomes

AF:

0.842

AC:

192609

AN:

228806

AF XY:

0.844

show subpopulations

Gnomad AFR exome

AF:

0.463

Gnomad AMR exome

AF:

0.911

Gnomad ASJ exome

AF:

0.826

Gnomad EAS exome

AF:

0.867

Gnomad FIN exome

AF:

0.888

Gnomad NFE exome

AF:

0.877

Gnomad OTH exome

AF:

0.843

GnomAD4 exome

AF:

0.868

AC:

1257195

AN:

1448158

Hom.:

549588

Cov.:

AF XY:

0.867

AC XY:

622904

AN XY:

718692

show subpopulations

African (AFR)

AF:

0.461

AC:

15365

AN:

33318

American (AMR)

AF:

0.904

AC:

39165

AN:

43304

Ashkenazi Jewish (ASJ)

AF:

0.824

AC:

21233

AN:

25766

East Asian (EAS)

AF:

0.876

AC:

34359

AN:

39220

South Asian (SAS)

AF:

0.785

AC:

66762

AN:

85100

European-Finnish (FIN)

AF:

0.889

AC:

45520

AN:

51222

Middle Eastern (MID)

AF:

0.756

AC:

4345

AN:

5744

European-Non Finnish (NFE)

AF:

0.887

AC:

979763

AN:

1104684

Other (OTH)

AF:

0.848

AC:

50683

AN:

59800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

10528

21056

31583

42111

52639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21254

42508

63762

85016

106270

<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:

0.763

AC:

116179

AN:

152216

Hom.:

46728

Cov.:

AF XY:

0.769

AC XY:

57211

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.478

AC:

19852

AN:

41506

American (AMR)

AF:

0.855

AC:

13096

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.837

AC:

2906

AN:

3472

East Asian (EAS)

AF:

0.869

AC:

4492

AN:

5168

South Asian (SAS)

AF:

0.784

AC:

3779

AN:

4820

European-Finnish (FIN)

AF:

0.894

AC:

9493

AN:

10620

Middle Eastern (MID)

AF:

0.745

AC:

219

AN:

294

European-Non Finnish (NFE)

AF:

0.880

AC:

59864

AN:

68004

Other (OTH)

AF:

0.779

AC:

1644

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1153

2307

3460

4614

5767

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

838

1676

2514

3352

4190

<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:

0.823

Hom.:

29276

Bravo

AF:

0.749

Asia WGS

AF:

0.805

AC:

2802

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jun 07, 2017

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 98% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 91. Only high quality variants are reported. -

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant nocturnal frontal lobe epilepsy 1

Benign:2

May 05, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.17

(source)

DANN

Benign

0.53

PhyloP100

-2.7

Mutation Taster

=100/0

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