Genetic Variant NM_000750.5:c.418A>G (chr15-78629887-T-C) – 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.418A>G(p.Ser140Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00967 in 1,612,488 control chromosomes in the GnomAD database, including 277 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 0.020 ( 64 hom., cov: 31)

Exomes 𝑓: 0.0086 ( 213 hom. )

Consequence

CHRNB4
NM_000750.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.09

Publications

18 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:

ENSG00000259555 (HGNC:):

ENSG00000259555 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 (MetaRNN=0.008622795).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.079 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5 link	c.418A>G	p.Ser140Gly	missense_variant	Exon 5 of 6	ENST00000261751.8	NP_000741.1	P30926-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB4	ENST00000261751.8 link	c.418A>G	p.Ser140Gly	missense_variant	Exon 5 of 6	1	NM_000750.5	ENSP00000261751.3		P30926-1

Frequencies

GnomAD3 genomes

AF:

0.0201

AC:

3053

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0464

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00766

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.0852

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00576

Gnomad OTH

AF:

0.0282

GnomAD2 exomes

AF:

0.0146

AC:

3635

AN:

249476

AF XY:

0.0137

show subpopulations

Gnomad AFR exome

AF:

0.0466

Gnomad AMR exome

AF:

0.00819

Gnomad ASJ exome

AF:

0.00160

Gnomad EAS exome

AF:

0.0801

Gnomad FIN exome

AF:

0.00488

Gnomad NFE exome

AF:

0.00591

Gnomad OTH exome

AF:

0.0126

GnomAD4 exome

AF:

0.00858

AC:

12536

AN:

1460248

Hom.:

213

Cov.:

AF XY:

0.00845

AC XY:

6138

AN XY:

726402

show subpopulations

African (AFR)

AF:

0.0461

AC:

1544

AN:

33480

American (AMR)

AF:

0.00819

AC:

366

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00153

AC:

AN:

26080

East Asian (EAS)

AF:

0.0736

AC:

2922

AN:

39698

South Asian (SAS)

AF:

0.00845

AC:

728

AN:

86200

European-Finnish (FIN)

AF:

0.00456

AC:

238

AN:

52196

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00515

AC:

5728

AN:

1111762

Other (OTH)

AF:

0.0148

AC:

891

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

719

1438

2157

2876

3595

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

282

564

846

1128

1410

<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:

0.0201

AC:

3060

AN:

152240

Hom.:

Cov.:

AF XY:

0.0205

AC XY:

1529

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0465

AC:

1932

AN:

41530

American (AMR)

AF:

0.00765

AC:

117

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00260

AC:

AN:

3466

East Asian (EAS)

AF:

0.0856

AC:

442

AN:

5164

South Asian (SAS)

AF:

0.0118

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00442

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00576

AC:

392

AN:

68022

Other (OTH)

AF:

0.0270

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

148

295

443

590

738

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0116

Hom.:

112

Bravo

AF:

0.0219

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.0446

AC:

196

ESP6500EA

AF:

0.00641

AC:

ExAC

AF:

0.0152

AC:

1844

Asia WGS

AF:

0.0360

AC:

124

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.42

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0086

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.2

PhyloP100

4.1

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.32

Sift

Benign

0.24

Sift4G

Benign

0.32

Polyphen

0.95

Vest4

0.23

MPC

0.89

ClinPred

0.042

GERP RS

5.0

Varity_R

0.53

gMVP

0.64

Mutation Taster

=75/25

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over