rs56069517

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_StrongBP7BS1BS2

The NM_000744.7(CHRNA4):c.1524C>T(p.Gly508Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,593,084 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 36 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.37

Publications

2 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=-0.55).

BP6

Variant 20-63349887-G-A is Benign according to our data. Variant chr20-63349887-G-A is described in ClinVar as Benign. ClinVar VariationId is 136760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.37 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00171 (2461/1440782) while in subpopulation SAS AF = 0.0186 (1563/84010). AF 95% confidence interval is 0.0178. There are 36 homozygotes in GnomAdExome4. There are 1649 alleles in the male GnomAdExome4 subpopulation. Median coverage is 83. This position passed quality control check.

BS2

High AC in GnomAd4 at 180 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA4	NM_000744.7 link	c.1524C>T	p.Gly508Gly	synonymous_variant	Exon 5 of 6	ENST00000370263.9	NP_000735.1	P43681-1B4DK78Q59FV0
CHRNA4	NM_001256573.2 link	c.996C>T	p.Gly332Gly	synonymous_variant	Exon 5 of 6		NP_001243502.1	P43681Q4VAQ3B4DK78Q59FV0
CHRNA4	NR_046317.2 link	n.1733C>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.1524C>T	p.Gly508Gly	synonymous_variant	Exon 5 of 6	1	NM_000744.7	ENSP00000359285.4		P43681-1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

179

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0153

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00304

AC:

691

AN:

227220

AF XY:

0.00398

show subpopulations

Gnomad AFR exome

AF:

0.000137

Gnomad AMR exome

AF:

0.000797

Gnomad ASJ exome

AF:

0.000561

Gnomad EAS exome

AF:

0.0000573

Gnomad FIN exome

AF:

0.0000529

Gnomad NFE exome

AF:

0.00136

Gnomad OTH exome

AF:

0.00216

GnomAD4 exome

AF:

0.00171

AC:

2461

AN:

1440782

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

1649

AN XY:

713786

show subpopulations

African (AFR)

AF:

0.000212

AC:

AN:

33080

American (AMR)

AF:

0.000857

AC:

AN:

43178

Ashkenazi Jewish (ASJ)

AF:

0.000672

AC:

AN:

25290

East Asian (EAS)

AF:

0.0000511

AC:

AN:

39172

South Asian (SAS)

AF:

0.0186

AC:

1563

AN:

84010

European-Finnish (FIN)

AF:

0.0000589

AC:

AN:

50936

Middle Eastern (MID)

AF:

0.00963

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

0.000594

AC:

654

AN:

1100212

Other (OTH)

AF:

0.00209

AC:

124

AN:

59296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

141

282

424

565

706

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00118

AC:

180

AN:

152302

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41572

American (AMR)

AF:

0.000849

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.0151

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

68002

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000964

Hom.:

Bravo

AF:

0.000808

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 17, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal dominant nocturnal frontal lobe epilepsy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 03, 2017

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.3

(source)

DANN

Benign

0.40

PhyloP100

1.4

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over