dbSNP rs56095004: CHRNB4:p.Arg136Pro (chr15-78629898-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000750.5(CHRNB4):c.407G>C(p.Arg136Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,134 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CHRNB4
NM_000750.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.244

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32588512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5 link	c.407G>C	p.Arg136Pro	missense_variant	Exon 5 of 6	ENST00000261751.8	NP_000741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB4	ENST00000261751.8 link	c.407G>C	p.Arg136Pro	missense_variant	Exon 5 of 6	1	NM_000750.5	ENSP00000261751.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725252

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25974

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

85984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111250

Other (OTH)

AF:

0.00

AC:

AN:

60338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

0.0013

BayesDel_noAF

Benign

-0.24

CADD

Benign

7.4

(source)

DANN

Benign

0.92

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.88

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.5

PhyloP100

-0.24

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.0

Sift

Benign

0.14

Sift4G

Benign

0.17

Vest4

0.33

ClinPred

0.18

GERP RS

0.57

Varity_R

0.66

gMVP

0.79

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over