Genetic Variant ENST00000558216.1:n.261+3254G>T (chr15-78704734-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The ENST00000558216.1(CHRNB4):n.261+3254G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,080 control chromosomes in the GnomAD database, including 7,792 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 0.29 ( 7792 hom., cov: 31)

Consequence

CHRNB4
ENST00000558216.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0260

Publications

12 publications found

Variant links:

Genes affected

CHRNB4 (HGNC:1964): (cholinergic receptor nicotinic beta 4 subunit) This gene is found within a conserved gene cluster and encodes one of the beta subunits of the nicotinic acetylcholine receptor (nAChRs) superfamily which form ligand-gated ion channels with a central pore that forms a cation channel. Neuronal nAChRs are pentameric structures that can be either homomeric or heteromeric, with heteromeric structures containing both alpha and beta subunits. Each subunit contains an extracellular amino terminus and four transmembrane domains. Nicotine is one of the agonists that binds to the receptor. Variants in this gene have been associated with nicotine dependence and lung cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2017]

CHRNB4 Gene-Disease associations (from GenCC):

lung cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CHRNB4 links:

ENSG00000290426 (HGNC:):

ENSG00000290426 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=-0.91).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
LOC105370913	XR_932508.2 link	n.1465+3254G>T	intron_variant	Intron 2 of 2
LOC105370913	XR_932509.2 link	n.1421+3254G>T	intron_variant	Intron 2 of 2
LOC105370913	XR_932510.3 link	n.567+3254G>T	intron_variant	Intron 2 of 2
LOC105370913	XR_932511.3 link	n.375+3254G>T	intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL
CHRNB4	ENST00000558216.1 link	n.261+3254G>T	intron_variant	Intron 2 of 2	2
CHRNB4	ENST00000560511.5 link	n.228+3254G>T	intron_variant	Intron 2 of 6	3
CHRNB4	ENST00000560868.1 link	n.65+3254G>T	intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.291

AC:

44250

AN:

151962

Hom.:

7787

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.357

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.343

Gnomad EAS

AF:

0.0510

Gnomad SAS

AF:

0.227

Gnomad FIN

AF:

0.330

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.409

Gnomad OTH

AF:

0.318

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.291

AC:

44264

AN:

152080

Hom.:

7792

Cov.:

AF XY:

0.286

AC XY:

21262

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.108

AC:

4469

AN:

41516

American (AMR)

AF:

0.315

AC:

4819

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

1191

AN:

3470

East Asian (EAS)

AF:

0.0513

AC:

266

AN:

5182

South Asian (SAS)

AF:

0.229

AC:

1105

AN:

4816

European-Finnish (FIN)

AF:

0.330

AC:

3490

AN:

10560

Middle Eastern (MID)

AF:

0.405

AC:

119

AN:

294

European-Non Finnish (NFE)

AF:

0.409

AC:

27816

AN:

67942

Other (OTH)

AF:

0.314

AC:

664

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1464

2928

4392

5856

7320

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

426

852

1278

1704

2130

<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:

0.355

Hom.:

1913

Bravo

AF:

0.284

Asia WGS

AF:

0.143

AC:

501

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.2

(source)

DANN

Benign

0.75

PhyloP100

-0.026

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over