dbSNP rs4809549: CHRNA4:n.1031+3124C>G (chr20-63370757-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000463705.5(CHRNA4):n.1031+3124C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 151,876 control chromosomes in the GnomAD database, including 15,926 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.45 ( 15924 hom., cov: 31)

Exomes 𝑓: 0.40 ( 2 hom. )

Consequence

CHRNA4
ENST00000463705.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.126

Publications

4 publications found

Variant links:

COSMIC-nc: COSV64718181

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC100130587	NR_110634.1 link	n.2948-104G>C		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CHRNA4	ENST00000463705.5 link	n.1031+3124C>G	intron_variant	Intron 3 of 4	1
CHRNA4	ENST00000475033.5 link	n.3656C>G	non_coding_transcript_exon_variant	Exon 4 of 4	2
ENSG00000203900	ENST00000370257.1 link	n.2948-104G>C	intron_variant	Intron 4 of 4	2
ENSG00000203900	ENST00000428531.1 link	n.325+185G>C	intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.453

AC:

68760

AN:

151738

Hom.:

15924

Cov.:

show subpopulations

Gnomad AFR

AF:

0.388

Gnomad AMI

AF:

0.641

Gnomad AMR

AF:

0.459

Gnomad ASJ

AF:

0.437

Gnomad EAS

AF:

0.621

Gnomad SAS

AF:

0.354

Gnomad FIN

AF:

0.473

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.481

Gnomad OTH

AF:

0.459

GnomAD4 exome

AF:

0.400

AC:

AN:

Hom.:

Cov.:

AF XY:

0.400

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.417

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.453

AC:

68773

AN:

151856

Hom.:

15924

Cov.:

AF XY:

0.451

AC XY:

33484

AN XY:

74198

show subpopulations

African (AFR)

AF:

0.387

AC:

16036

AN:

41396

American (AMR)

AF:

0.459

AC:

6994

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.437

AC:

1515

AN:

3470

East Asian (EAS)

AF:

0.620

AC:

3188

AN:

5138

South Asian (SAS)

AF:

0.353

AC:

1695

AN:

4808

European-Finnish (FIN)

AF:

0.473

AC:

4995

AN:

10554

Middle Eastern (MID)

AF:

0.452

AC:

133

AN:

294

European-Non Finnish (NFE)

AF:

0.481

AC:

32675

AN:

67928

Other (OTH)

AF:

0.455

AC:

957

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1908

3817

5725

7634

9542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

638

1276

1914

2552

3190

<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:

0.346

Hom.:

920

Bravo

AF:

0.457

Asia WGS

AF:

0.435

AC:

1512

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.9

(source)

DANN

Benign

0.74

PhyloP100

-0.13

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over