Variant rs56095004 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000750.5(CHRNB4):c.407G>A(p.Arg136Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 1,610,264 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R136W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0054 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0082 ( 55 hom. )

Consequence

CHRNB4
NM_000750.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.244

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0066691935).

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5 link	c.407G>A	p.Arg136Gln	missense_variant	Exon 5 of 6	ENST00000261751.8	NP_000741.1	P30926-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHRNB4	ENST00000261751.8 link	c.407G>A	p.Arg136Gln	missense_variant	Exon 5 of 6	1	NM_000750.5	ENSP00000261751.3	P30926-1
CHRNB4	ENST00000412074.6 link	c.359+1178G>A		intron_variant	Intron 4 of 4	1		ENSP00000416386.2	P30926-2
CHRNB4	ENST00000559849.5 link	n.*463G>A		non_coding_transcript_exon_variant	Exon 12 of 12	1		ENSP00000457404.1	H3BU02
CHRNB4	ENST00000559849.5 link	n.*463G>A		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000457404.1	H3BU02

Frequencies

GnomAD3 genomes

AF:

0.00539

AC:

820

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00315

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00996

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00915

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00560

AC:

1384

AN:

247178

Hom.:

AF XY:

0.00598

AC XY:

800

AN XY:

133768

show subpopulations

Gnomad AFR exome

AF:

0.00163

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.00658

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00805

Gnomad FIN exome

AF:

0.00101

Gnomad NFE exome

AF:

0.00824

Gnomad OTH exome

AF:

0.00513

GnomAD4 exome

AF:

0.00818

AC:

11929

AN:

1458128

Hom.:

Cov.:

AF XY:

0.00812

AC XY:

5889

AN XY:

725248

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00238

Gnomad4 ASJ exome

AF:

0.00670

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00785

Gnomad4 FIN exome

AF:

0.00170

Gnomad4 NFE exome

AF:

0.00939

Gnomad4 OTH exome

AF:

0.00676

GnomAD4 genome

AF:

0.00539

AC:

820

AN:

152136

Hom.:

Cov.:

AF XY:

0.00493

AC XY:

367

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00997

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00915

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00773

Hom.:

Bravo

AF:

0.00526

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00757

AC:

ExAC

AF:

0.00565

AC:

686

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00840

EpiControl

AF:

0.00854

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.6

DANN

Benign

0.94

DEOGEN2

Benign

0.14

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.16

M_CAP

Benign

0.024

MetaRNN

Benign

0.0067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.86

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.15

REVEL

Benign

0.12

Sift

Benign

0.30

Sift4G

Benign

0.30

Polyphen

0.0010

Vest4

0.019

MVP

0.45

MPC

0.35

ClinPred

0.00092

GERP RS

0.57

Varity_R

0.037

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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