dbSNP rs12914008: CHRNB4:p.Thr91Ile (chr15-78631163-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000750.5(CHRNB4):c.272C>T(p.Thr91Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0373 in 1,614,048 control chromosomes in the GnomAD database, including 1,340 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.025 ( 70 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1270 hom. )

Consequence

CHRNB4
NM_000750.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.38

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013037175).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0251 (3817/152308) while in subpopulation NFE AF= 0.0419 (2848/68016). AF 95% confidence interval is 0.0406. There are 70 homozygotes in gnomad4. There are 1785 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 70 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5 link	c.272C>T	p.Thr91Ile	missense_variant	Exon 4 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.272C>T	p.Thr91Ile	missense_variant	Exon 4 of 6	1	NM_000750.5	ENSP00000261751.3		P30926-1

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3817

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00758

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0164

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00683

Gnomad FIN

AF:

0.0238

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0419

Gnomad OTH

AF:

0.0225

GnomAD3 exomes

AF:

0.0241

AC:

6058

AN:

251476

Hom.:

100

AF XY:

0.0246

AC XY:

3338

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.0163

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00728

Gnomad FIN exome

AF:

0.0267

Gnomad NFE exome

AF:

0.0394

Gnomad OTH exome

AF:

0.0257

GnomAD4 exome

AF:

0.0385

AC:

56345

AN:

1461740

Hom.:

1270

Cov.:

AF XY:

0.0375

AC XY:

27243

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00633

Gnomad4 AMR exome

AF:

0.0105

Gnomad4 ASJ exome

AF:

0.0152

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00794

Gnomad4 FIN exome

AF:

0.0258

Gnomad4 NFE exome

AF:

0.0462

Gnomad4 OTH exome

AF:

0.0304

GnomAD4 genome

AF:

0.0251

AC:

3817

AN:

152308

Hom.:

Cov.:

AF XY:

0.0240

AC XY:

1785

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00755

Gnomad4 AMR

AF:

0.0164

Gnomad4 ASJ

AF:

0.0173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00684

Gnomad4 FIN

AF:

0.0238

Gnomad4 NFE

AF:

0.0419

Gnomad4 OTH

AF:

0.0222

Alfa

AF:

0.0362

Hom.:

189

Bravo

AF:

0.0244

TwinsUK

AF:

0.0477

AC:

177

ALSPAC

AF:

0.0511

AC:

197

ESP6500AA

AF:

0.00751

AC:

ESP6500EA

AF:

0.0440

AC:

378

ExAC

AF:

0.0238

AC:

2892

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0379

EpiControl

AF:

0.0366

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

1.6

L;L

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.3

N;N

REVEL

Benign

0.27

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.014

D;T

Polyphen

0.058

B;.

Vest4

0.081

MPC

0.40

ClinPred

0.017

GERP RS

4.3

Varity_R

0.25

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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