rs1044396

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.1629C>T(p.Ser543Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,609,060 control chromosomes in the GnomAD database, including 220,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 15024 hom., cov: 34)

Exomes 𝑓: 0.52 ( 205217 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.929

Publications

126 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=-0.9).

BP6

Variant 20-63349782-G-A is Benign according to our data. Variant chr20-63349782-G-A is described in ClinVar as Benign. ClinVar VariationId is 93427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.929 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHRNA4	NM_000744.7 link	c.1629C>T	p.Ser543Ser	synonymous_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2 link	c.1101C>T	p.Ser367Ser	synonymous_variant	Exon 5 of 6		NP_001243502.1
CHRNA4	NR_046317.2 link	n.1838C>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.1629C>T	p.Ser543Ser	synonymous_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes

AF:

0.404

AC:

61427

AN:

152032

Hom.:

15016

Cov.:

show subpopulations

Gnomad AFR

AF:

0.128

Gnomad AMI

AF:

0.379

Gnomad AMR

AF:

0.498

Gnomad ASJ

AF:

0.432

Gnomad EAS

AF:

0.253

Gnomad SAS

AF:

0.424

Gnomad FIN

AF:

0.524

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.541

Gnomad OTH

AF:

0.413

GnomAD2 exomes

AF:

0.471

AC:

116275

AN:

247118

AF XY:

0.475

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.528

Gnomad ASJ exome

AF:

0.431

Gnomad EAS exome

AF:

0.257

Gnomad FIN exome

AF:

0.530

Gnomad NFE exome

AF:

0.539

Gnomad OTH exome

AF:

0.486

GnomAD4 exome

AF:

0.523

AC:

761794

AN:

1456910

Hom.:

205217

Cov.:

AF XY:

0.521

AC XY:

376959

AN XY:

724028

show subpopulations

African (AFR)

AF:

0.108

AC:

3612

AN:

33346

American (AMR)

AF:

0.526

AC:

23426

AN:

44518

Ashkenazi Jewish (ASJ)

AF:

0.424

AC:

11040

AN:

26034

East Asian (EAS)

AF:

0.272

AC:

10778

AN:

39556

South Asian (SAS)

AF:

0.438

AC:

37716

AN:

86122

European-Finnish (FIN)

AF:

0.529

AC:

27595

AN:

52120

Middle Eastern (MID)

AF:

0.391

AC:

2253

AN:

5760

European-Non Finnish (NFE)

AF:

0.555

AC:

616019

AN:

1109294

Other (OTH)

AF:

0.488

AC:

29355

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

20896

41793

62689

83586

104482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17098

34196

51294

68392

85490

<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:

0.404

AC:

61447

AN:

152150

Hom.:

15024

Cov.:

AF XY:

0.408

AC XY:

30309

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.128

AC:

5316

AN:

41528

American (AMR)

AF:

0.498

AC:

7621

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

1498

AN:

3470

East Asian (EAS)

AF:

0.253

AC:

1310

AN:

5178

South Asian (SAS)

AF:

0.426

AC:

2051

AN:

4818

European-Finnish (FIN)

AF:

0.524

AC:

5553

AN:

10592

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.541

AC:

36759

AN:

67948

Other (OTH)

AF:

0.416

AC:

880

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1639

3278

4916

6555

8194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

568

1136

1704

2272

2840

<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:

0.497

Hom.:

50885

Bravo

AF:

0.388

Asia WGS

AF:

0.348

AC:

1212

AN:

3478

EpiCase

AF:

0.527

EpiControl

AF:

0.521

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

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 74% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 69. Only high quality variants are reported.

Apr 12, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28877969)

Apr 28, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal dominant nocturnal frontal lobe epilepsy 1

Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

NICOTINE ADDICTION, PROTECTION AGAINST

Benign:1

Jul 01, 2004

OMIM

Significance:protective

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.51

(source)

DANN

Benign

0.61

PhyloP100

-0.93

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