Genetic Variant CHRNA4:p.Ala553Ala (chr20-63349752-C-T) – ACMG Classification: Benign (-21 pts)

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.1659G>A(p.Ala553Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,611,664 control chromosomes in the GnomAD database, including 222,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 15300 hom., cov: 34)

Exomes 𝑓: 0.53 ( 207278 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.63

Publications

47 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 20-63349752-C-T is Benign according to our data. Variant chr20-63349752-C-T is described in ClinVar as Benign. ClinVar VariationId is 93428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.63 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000744.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA4	NM_000744.7	MANE Select	c.1659G>A	p.Ala553Ala	synonymous	Exon 5 of 6	NP_000735.1
CHRNA4	NM_001256573.2		c.1131G>A	p.Ala377Ala	synonymous	Exon 5 of 6	NP_001243502.1
CHRNA4	NR_046317.2		n.1868G>A		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.1659G>A	p.Ala553Ala	synonymous	Exon 5 of 6	ENSP00000359285.4
CHRNA4	ENST00000463705.5	TSL:1	n.2307G>A		non_coding_transcript_exon	Exon 4 of 5
CHRNA4	ENST00000467563.3	TSL:1	n.1729G>A		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes

AF:

0.410

AC:

62297

AN:

152040

Hom.:

15290

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.378

Gnomad AMR

AF:

0.501

Gnomad ASJ

AF:

0.432

Gnomad EAS

AF:

0.380

Gnomad SAS

AF:

0.428

Gnomad FIN

AF:

0.527

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.542

Gnomad OTH

AF:

0.417

GnomAD2 exomes

AF:

0.482

AC:

119354

AN:

247732

AF XY:

0.485

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.530

Gnomad ASJ exome

AF:

0.431

Gnomad EAS exome

AF:

0.390

Gnomad FIN exome

AF:

0.533

Gnomad NFE exome

AF:

0.540

Gnomad OTH exome

AF:

0.492

GnomAD4 exome

AF:

0.527

AC:

768498

AN:

1459506

Hom.:

207278

Cov.:

AF XY:

0.524

AC XY:

380500

AN XY:

725962

show subpopulations

African (AFR)

AF:

0.109

AC:

3644

AN:

33450

American (AMR)

AF:

0.527

AC:

23547

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.424

AC:

11055

AN:

26076

East Asian (EAS)

AF:

0.399

AC:

15825

AN:

39664

South Asian (SAS)

AF:

0.441

AC:

38025

AN:

86200

European-Finnish (FIN)

AF:

0.531

AC:

27719

AN:

52156

Middle Eastern (MID)

AF:

0.391

AC:

2252

AN:

5764

European-Non Finnish (NFE)

AF:

0.555

AC:

616475

AN:

1111234

Other (OTH)

AF:

0.497

AC:

29956

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

20846

41692

62537

83383

104229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17140

34280

51420

68560

85700

<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:

0.410

AC:

62316

AN:

152158

Hom.:

15300

Cov.:

AF XY:

0.414

AC XY:

30808

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.129

AC:

5379

AN:

41542

American (AMR)

AF:

0.501

AC:

7656

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

1498

AN:

3470

East Asian (EAS)

AF:

0.380

AC:

1959

AN:

5152

South Asian (SAS)

AF:

0.429

AC:

2069

AN:

4818

European-Finnish (FIN)

AF:

0.527

AC:

5591

AN:

10600

Middle Eastern (MID)

AF:

0.381

AC:

112

AN:

294

European-Non Finnish (NFE)

AF:

0.542

AC:

36820

AN:

67978

Other (OTH)

AF:

0.422

AC:

888

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1661

3322

4983

6644

8305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<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:

0.492

Hom.:

12797

Bravo

AF:

0.394

Asia WGS

AF:

0.393

AC:

1370

AN:

3478

EpiCase

AF:

0.527

EpiControl

AF:

0.520

ClinVar

Significance: Benign

Submissions summary: Benign:11

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 75% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 70. 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.

Apr 12, 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

not provided

Benign:3

Apr 28, 2017

Athena Diagnostics

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

Mar 03, 2015

GeneDx

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.057

(source)

DANN

Benign

0.58

PhyloP100

-3.6

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over