20-63350733-A-G

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.678T>C(p.Cys226Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 1,604,470 control chromosomes in the GnomAD database, including 666,892 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 49090 hom., cov: 27)

Exomes 𝑓: 0.92 ( 617802 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.186

Publications

38 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=-0.73).

BP6

Variant 20-63350733-A-G is Benign according to our data. Variant chr20-63350733-A-G is described in ClinVar as Benign. ClinVar VariationId is 128750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.186 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7 link	c.678T>C	p.Cys226Cys	synonymous_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1	P43681-1B4DK78Q59FV0
CHRNA4	NM_001256573.2 link	c.150T>C	p.Cys50Cys	synonymous_variant	Exon 5 of 6		NP_001243502.1	P43681Q4VAQ3B4DK78Q59FV0
CHRNA4	NR_046317.2 link	n.887T>C		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.678T>C	p.Cys226Cys	synonymous_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4		P43681-1

Frequencies

GnomAD3 genomes

AF:

0.829

AC:

118747

AN:

143160

Hom.:

49067

Cov.:

show subpopulations

Gnomad AFR

AF:

0.646

Gnomad AMI

AF:

0.962

Gnomad AMR

AF:

0.886

Gnomad ASJ

AF:

0.840

Gnomad EAS

AF:

0.952

Gnomad SAS

AF:

0.922

Gnomad FIN

AF:

0.932

Gnomad MID

AF:

0.836

Gnomad NFE

AF:

0.893

Gnomad OTH

AF:

0.840

GnomAD2 exomes

AF:

0.923

AC:

231165

AN:

250536

AF XY:

0.927

show subpopulations

Gnomad AFR exome

AF:

0.644

Gnomad AMR exome

AF:

0.952

Gnomad ASJ exome

AF:

0.893

Gnomad EAS exome

AF:

0.982

Gnomad FIN exome

AF:

0.943

Gnomad NFE exome

AF:

0.936

Gnomad OTH exome

AF:

0.923

GnomAD4 exome

AF:

0.920

AC:

1343602

AN:

1461194

Hom.:

617802

Cov.:

AF XY:

0.920

AC XY:

668587

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.632

AC:

21138

AN:

33430

American (AMR)

AF:

0.916

AC:

40945

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.878

AC:

22937

AN:

26120

East Asian (EAS)

AF:

0.938

AC:

37227

AN:

39678

South Asian (SAS)

AF:

0.909

AC:

78316

AN:

86176

European-Finnish (FIN)

AF:

0.933

AC:

49627

AN:

53200

Middle Eastern (MID)

AF:

0.913

AC:

5263

AN:

5764

European-Non Finnish (NFE)

AF:

0.929

AC:

1033352

AN:

1111760

Other (OTH)

AF:

0.908

AC:

54797

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.562

Heterozygous variant carriers

6533

13065

19598

26130

32663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21558

43116

64674

86232

107790

<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:

0.829

AC:

118826

AN:

143276

Hom.:

49090

Cov.:

AF XY:

0.839

AC XY:

59010

AN XY:

70344

show subpopulations

African (AFR)

AF:

0.646

AC:

25031

AN:

38770

American (AMR)

AF:

0.886

AC:

12837

AN:

14486

Ashkenazi Jewish (ASJ)

AF:

0.840

AC:

2712

AN:

3230

East Asian (EAS)

AF:

0.952

AC:

4609

AN:

4842

South Asian (SAS)

AF:

0.922

AC:

4242

AN:

4600

European-Finnish (FIN)

AF:

0.932

AC:

9597

AN:

10292

Middle Eastern (MID)

AF:

0.844

AC:

211

AN:

250

European-Non Finnish (NFE)

AF:

0.893

AC:

57066

AN:

63932

Other (OTH)

AF:

0.841

AC:

1701

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.586

Heterozygous variant carriers

764

1527

2291

3054

3818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

842

1684

2526

3368

4210

<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:

0.897

Hom.:

103058

Bravo

AF:

0.849

Asia WGS

AF:

0.915

AC:

3181

AN:

3478

EpiCase

AF:

0.935

EpiControl

AF:

0.929

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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 100% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 93. Only high quality variants are reported. -

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:3

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

- -

May 24, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.10

(source)

DANN

Benign

0.44

PhyloP100

-0.19

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