Genetic Variant CHRNB4:p.Pro356Pro (chr15-78629237-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_000750.5(CHRNB4):c.1068G>A(p.Pro356Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,613,392 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 3 hom. )

Consequence

CHRNB4
NM_000750.5 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.515

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:

ENSG00000259555 (HGNC:):

ENSG00000259555 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 15-78629237-C-T is Benign according to our data. Variant chr15-78629237-C-T is described in ClinVar as [Benign]. Clinvar id is 718587.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.515 with no splicing effect.

BS2

High AC in GnomAd4 at 307 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5 link	c.1068G>A	p.Pro356Pro	synonymous_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.1068G>A	p.Pro356Pro	synonymous_variant	Exon 5 of 6	1	NM_000750.5	ENSP00000261751.3	P30926-1
CHRNB4	ENST00000412074.6 link	c.359+1839G>A		intron_variant	Intron 4 of 4	1		ENSP00000416386.2	P30926-2
ENSG00000259555	ENST00000821537.1 link	n.312+1672C>T		intron_variant	Intron 2 of 2
CHRNB4	ENST00000559849.5 link	n.*1124G>A		downstream_gene_variant		1		ENSP00000457404.1	H3BU02

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

307

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00715

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000562

AC:

141

AN:

250678

AF XY:

0.000406

show subpopulations

Gnomad AFR exome

AF:

0.00752

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000222

AC:

325

AN:

1461186

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

726772

show subpopulations

African (AFR)

AF:

0.00774

AC:

259

AN:

33476

American (AMR)

AF:

0.000358

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111578

Other (OTH)

AF:

0.000613

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00202

AC:

307

AN:

152206

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

138

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00712

AC:

296

AN:

41546

American (AMR)

AF:

0.000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00176

Hom.:

Bravo

AF:

0.00237

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.95

(source)

DANN

Benign

0.70

PhyloP100

-0.52

Mutation Taster

=100/0

polymorphism

(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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chr15-78629237-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over