rs2273506

Variant names:

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.189C>T(p.Leu63Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0793 in 1,612,634 control chromosomes in the GnomAD database, including 5,925 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.096 ( 747 hom., cov: 34)

Exomes 𝑓: 0.078 ( 5178 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.33

Publications

18 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=-0.86).

BP6

Variant 20-63359587-G-A is Benign according to our data. Variant chr20-63359587-G-A is described in ClinVar as Benign. ClinVar VariationId is 128747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHRNA4	NM_000744.7 link	c.189C>T	p.Leu63Leu	synonymous_variant	Exon 2 of 6	ENST00000370263.9	NP_000735.1
CHRNA4	NM_001256573.2 link	c.-358C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 6		NP_001243502.1
CHRNA4	NR_046317.2 link	n.373C>T		non_coding_transcript_exon_variant	Exon 2 of 6
CHRNA4	NM_001256573.2 link	c.-358C>T		5_prime_UTR_variant	Exon 2 of 6		NP_001243502.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA4	ENST00000370263.9 link	c.189C>T	p.Leu63Leu	synonymous_variant	Exon 2 of 6	1	NM_000744.7	ENSP00000359285.4

Frequencies

GnomAD3 genomes

AF:

0.0957

AC:

14561

AN:

152168

Hom.:

745

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.0811

Gnomad AMR

AF:

0.0764

Gnomad ASJ

AF:

0.0884

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.0873

Gnomad MID

AF:

0.184

Gnomad NFE

AF:

0.0712

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.0924

AC:

23078

AN:

249840

AF XY:

0.0953

show subpopulations

Gnomad AFR exome

AF:

0.134

Gnomad AMR exome

AF:

0.0478

Gnomad ASJ exome

AF:

0.0963

Gnomad EAS exome

AF:

0.130

Gnomad FIN exome

AF:

0.0886

Gnomad NFE exome

AF:

0.0746

Gnomad OTH exome

AF:

0.0913

GnomAD4 exome

AF:

0.0776

AC:

113252

AN:

1460348

Hom.:

5178

Cov.:

AF XY:

0.0799

AC XY:

58052

AN XY:

726460

show subpopulations

African (AFR)

AF:

0.142

AC:

4739

AN:

33476

American (AMR)

AF:

0.0510

AC:

2281

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

2638

AN:

26128

East Asian (EAS)

AF:

0.122

AC:

4856

AN:

39694

South Asian (SAS)

AF:

0.160

AC:

13826

AN:

86258

European-Finnish (FIN)

AF:

0.0869

AC:

4525

AN:

52082

Middle Eastern (MID)

AF:

0.167

AC:

959

AN:

5756

European-Non Finnish (NFE)

AF:

0.0668

AC:

74321

AN:

1111878

Other (OTH)

AF:

0.0846

AC:

5107

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

6582

13163

19745

26326

32908

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2874

5748

8622

11496

14370

<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:

0.0958

AC:

14584

AN:

152286

Hom.:

747

Cov.:

AF XY:

0.0967

AC XY:

7199

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.133

AC:

5535

AN:

41540

American (AMR)

AF:

0.0764

AC:

1170

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0884

AC:

307

AN:

3472

East Asian (EAS)

AF:

0.128

AC:

664

AN:

5190

South Asian (SAS)

AF:

0.163

AC:

787

AN:

4822

European-Finnish (FIN)

AF:

0.0873

AC:

927

AN:

10616

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0712

AC:

4846

AN:

68024

Other (OTH)

AF:

0.103

AC:

217

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

707

1413

2120

2826

3533

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<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:

0.0848

Hom.:

1007

Bravo

AF:

0.0942

Asia WGS

AF:

0.145

AC:

502

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant nocturnal frontal lobe epilepsy 1

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

Apr 11, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

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 22% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 20. Only high quality variants are reported. -

not provided

Benign:2

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

- -

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

Mar 02, 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

-0.86

CADD

Benign

0.13

(source)

DANN

Benign

0.93

PhyloP100

-3.3

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