Variant 15-78625231-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000750.5(CHRNB4):c.1399A>G(p.Met467Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,586,456 control chromosomes in the GnomAD database, including 260 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.024 ( 164 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 96 hom. )

Consequence

CHRNB4
NM_000750.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.75

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022334754).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB4	NM_000750.5 linkuse as main transcript	c.1399A>G	p.Met467Val	missense_variant	6/6	ENST00000261751.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB4	ENST00000261751.8 linkuse as main transcript	c.1399A>G	p.Met467Val	missense_variant	6/6	1	NM_000750.5	P1	P30926-1
CHRNB4	ENST00000412074.6 linkuse as main transcript	c.420A>G	p.Ser140=	synonymous_variant	5/5	1			P30926-2

Frequencies

GnomAD3 genomes

AF:

0.0243

AC:

3692

AN:

152054

Hom.:

164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0843

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00871

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0220

GnomAD3 exomes

AF:

0.00665

AC:

1520

AN:

228484

Hom.:

AF XY:

0.00514

AC XY:

635

AN XY:

123604

show subpopulations

Gnomad AFR exome

AF:

0.0845

Gnomad AMR exome

AF:

0.00485

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000180

Gnomad OTH exome

AF:

0.00241

GnomAD4 exome

AF:

0.00223

AC:

3195

AN:

1434284

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

1360

AN XY:

711654

show subpopulations

Gnomad4 AFR exome

AF:

0.0775

Gnomad4 AMR exome

AF:

0.00449

Gnomad4 ASJ exome

AF:

0.0000414

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000265

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000128

Gnomad4 OTH exome

AF:

0.00569

GnomAD4 genome

AF:

0.0244

AC:

3707

AN:

152172

Hom.:

164

Cov.:

AF XY:

0.0245

AC XY:

1825

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.0844

Gnomad4 AMR

AF:

0.00870

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.0218

Alfa

AF:

0.00489

Hom.:

Bravo

AF:

0.0276

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0831

AC:

365

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00778

AC:

944

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.12

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.44

PROVEAN

Benign

1.6

REVEL

Benign

0.24

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.13

MVP

0.39

MPC

0.31

ClinPred

0.00079

GERP RS

3.5

Varity_R

0.078

gMVP

0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over