Genetic Variant NM_000744.7:c.51G>A (chr20-63361115-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.51G>A(p.Leu17Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0777 in 1,477,178 control chromosomes in the GnomAD database, including 4,862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.059 ( 355 hom., cov: 32)

Exomes 𝑓: 0.080 ( 4507 hom. )

Consequence

CHRNA4
NM_000744.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0920

Publications

9 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:

ENSG00000203900 (HGNC:):

ENSG00000203900 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=-0.64).

BP6

Variant 20-63361115-C-T is Benign according to our data. Variant chr20-63361115-C-T is described in ClinVar as Benign. ClinVar VariationId is 93430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.092 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0838 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.51G>A	p.Leu17Leu	synonymous	Exon 1 of 6	NP_000735.1
CHRNA4	NR_046317.2		n.235G>A		non_coding_transcript_exon	Exon 1 of 6
CHRNA4	NM_001256573.2		c.-471+62G>A		intron	N/A	NP_001243502.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHRNA4	ENST00000370263.9	TSL:1 MANE Select	c.51G>A	p.Leu17Leu	synonymous	Exon 1 of 6	ENSP00000359285.4
CHRNA4	ENST00000627000.1	TSL:1	n.51G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000486914.1
CHRNA4	ENST00000463705.5	TSL:1	n.1032-10088G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0588

AC:

8925

AN:

151852

Hom.:

355

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0145

Gnomad AMI

AF:

0.0442

Gnomad AMR

AF:

0.0463

Gnomad ASJ

AF:

0.0986

Gnomad EAS

AF:

0.000394

Gnomad SAS

AF:

0.0332

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.0510

Gnomad NFE

AF:

0.0856

Gnomad OTH

AF:

0.0610

GnomAD2 exomes

AF:

0.0605

AC:

5163

AN:

85354

AF XY:

0.0615

show subpopulations

Gnomad AFR exome

AF:

0.00679

Gnomad AMR exome

AF:

0.0303

Gnomad ASJ exome

AF:

0.0789

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0973

Gnomad NFE exome

AF:

0.0873

Gnomad OTH exome

AF:

0.0601

GnomAD4 exome

AF:

0.0799

AC:

105881

AN:

1325218

Hom.:

4507

Cov.:

AF XY:

0.0794

AC XY:

51831

AN XY:

652696

show subpopulations

African (AFR)

AF:

0.0109

AC:

294

AN:

26888

American (AMR)

AF:

0.0350

AC:

996

AN:

28438

Ashkenazi Jewish (ASJ)

AF:

0.0851

AC:

2003

AN:

23524

East Asian (EAS)

AF:

0.000101

AC:

AN:

29814

South Asian (SAS)

AF:

0.0428

AC:

3135

AN:

73210

European-Finnish (FIN)

AF:

0.0972

AC:

3152

AN:

32430

Middle Eastern (MID)

AF:

0.0550

AC:

219

AN:

3980

European-Non Finnish (NFE)

AF:

0.0877

AC:

92227

AN:

1051928

Other (OTH)

AF:

0.0700

AC:

3852

AN:

55006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

4571

9142

13713

18284

22855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3398

6796

10194

13592

16990

<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:

0.0587

AC:

8920

AN:

151960

Hom.:

355

Cov.:

AF XY:

0.0581

AC XY:

4318

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.0145

AC:

601

AN:

41508

American (AMR)

AF:

0.0461

AC:

705

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0986

AC:

342

AN:

3468

East Asian (EAS)

AF:

0.000395

AC:

AN:

5066

South Asian (SAS)

AF:

0.0332

AC:

160

AN:

4818

European-Finnish (FIN)

AF:

0.105

AC:

1115

AN:

10610

Middle Eastern (MID)

AF:

0.0445

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0857

AC:

5815

AN:

67892

Other (OTH)

AF:

0.0604

AC:

127

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

426

852

1279

1705

2131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.0457

Hom.:

Bravo

AF:

0.0528

Asia WGS

AF:

0.0160

AC:

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 09, 2017

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: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 1

Benign:1

Apr 11, 2017

Athena Diagnostics

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

Feb 22, 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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

0.092

PromoterAI

-0.013

Neutral

(source)

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

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