Genetic Variant CHRNB4:p.Ile295Ile (chr15-78629420-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_000750.5(CHRNB4):c.885C>T(p.Ile295Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,614,072 control chromosomes in the GnomAD database, including 571 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 0.035 ( 236 hom., cov: 31)

Exomes 𝑓: 0.010 ( 335 hom. )

Consequence

CHRNB4
NM_000750.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.187

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP7

Synonymous conserved (PhyloP=-0.187 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.096 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5 link	c.885C>T	p.Ile295Ile	synonymous_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.885C>T	p.Ile295Ile	synonymous_variant	Exon 5 of 6	1	NM_000750.5	ENSP00000261751.3		P30926-1

Frequencies

GnomAD3 genomes

AF:

0.0351

AC:

5335

AN:

152090

Hom.:

235

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0983

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0140

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.0832

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00609

Gnomad OTH

AF:

0.0425

GnomAD2 exomes

AF:

0.0184

AC:

4625

AN:

251386

AF XY:

0.0164

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.0783

Gnomad FIN exome

AF:

0.00491

Gnomad NFE exome

AF:

0.00624

Gnomad OTH exome

AF:

0.0143

GnomAD4 exome

AF:

0.0101

AC:

14710

AN:

1461864

Hom.:

335

Cov.:

AF XY:

0.00968

AC XY:

7040

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0967

AC:

3236

AN:

33480

American (AMR)

AF:

0.0122

AC:

547

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00153

AC:

AN:

26136

East Asian (EAS)

AF:

0.0720

AC:

2857

AN:

39700

South Asian (SAS)

AF:

0.00709

AC:

612

AN:

86258

European-Finnish (FIN)

AF:

0.00453

AC:

242

AN:

53392

Middle Eastern (MID)

AF:

0.0213

AC:

123

AN:

5768

European-Non Finnish (NFE)

AF:

0.00535

AC:

5944

AN:

1112010

Other (OTH)

AF:

0.0184

AC:

1109

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1024

2049

3073

4098

5122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

318

636

954

1272

1590

<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:

0.0352

AC:

5353

AN:

152208

Hom.:

236

Cov.:

AF XY:

0.0354

AC XY:

2634

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0985

AC:

4087

AN:

41490

American (AMR)

AF:

0.0140

AC:

214

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.0836

AC:

432

AN:

5166

South Asian (SAS)

AF:

0.0112

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00442

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00609

AC:

414

AN:

68020

Other (OTH)

AF:

0.0412

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

247

494

740

987

1234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0177

Hom.:

140

Bravo

AF:

0.0389

Asia WGS

AF:

0.0380

AC:

132

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.66

(source)

DANN

Benign

0.82

PhyloP100

-0.19

Mutation Taster

=93/7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over