Genetic Variant CHRNB4:c.56-1549A>C (chr15-78637136-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_000750.5(CHRNB4):c.56-1549A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 152,048 control chromosomes in the GnomAD database, including 32,598 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 0.62 ( 32598 hom., cov: 31)

Consequence

CHRNB4
NM_000750.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.967

Publications

24 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:

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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=-0.88).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000750.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB4	NM_000750.5	MANE Select	c.56-1549A>C		intron	N/A	NP_000741.1	P30926-1
	CHRNB4	NM_001256567.3		c.56-1549A>C		intron	N/A	NP_001243496.1	P30926-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHRNB4	ENST00000261751.8	TSL:1 MANE Select	c.56-1549A>C	intron	N/A	ENSP00000261751.3	P30926-1
CHRNB4	ENST00000412074.6	TSL:1	c.56-1549A>C	intron	N/A	ENSP00000416386.2	P30926-2
CHRNB4	ENST00000559849.5	TSL:1	n.47-1549A>C	intron	N/A	ENSP00000457404.1	H3BU02

Frequencies

GnomAD3 genomes

AF:

0.624

AC:

94820

AN:

151930

Hom.:

32594

Cov.:

show subpopulations

Gnomad AFR

AF:

0.384

Gnomad AMI

AF:

0.742

Gnomad AMR

AF:

0.529

Gnomad ASJ

AF:

0.776

Gnomad EAS

AF:

0.212

Gnomad SAS

AF:

0.534

Gnomad FIN

AF:

0.714

Gnomad MID

AF:

0.649

Gnomad NFE

AF:

0.805

Gnomad OTH

AF:

0.636

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

GnomAD4 genome

AF:

0.624

AC:

94853

AN:

152048

Hom.:

32598

Cov.:

AF XY:

0.615

AC XY:

45749

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.384

AC:

15934

AN:

41452

American (AMR)

AF:

0.529

AC:

8076

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.776

AC:

2694

AN:

3470

East Asian (EAS)

AF:

0.212

AC:

1094

AN:

5168

South Asian (SAS)

AF:

0.534

AC:

2574

AN:

4820

European-Finnish (FIN)

AF:

0.714

AC:

7552

AN:

10574

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.805

AC:

54736

AN:

67976

Other (OTH)

AF:

0.629

AC:

1328

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1529

3059

4588

6118

7647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

750

1500

2250

3000

3750

<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:

0.710

Hom.:

16796

Bravo

AF:

0.592

Asia WGS

AF:

0.370

AC:

1289

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.79

(source)

DANN

Benign

0.78

PhyloP100

-0.97

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over