15-78636536-A-G

Variant names:

• chr15-78636536-A-G
• rs11636605
• NM_000750.5:c.56-949T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000750.5(CHRNB4):​c.56-949T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 151,594 control chromosomes in the GnomAD database, including 32,584 homozygotes. 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: 𝑓 0.63 (32584 hom., cov: 30)
• Consequence: CHRNB4 NM_000750.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.494
• Publications: 21 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5	c.56-949T>C		intron_variant	Intron 1 of 5	ENST00000261751.8	NP_000741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB4	ENST00000261751.8	c.56-949T>C		intron_variant	Intron 1 of 5	1	NM_000750.5	ENSP00000261751.3
CHRNB4	ENST00000412074.6	c.56-949T>C		intron_variant	Intron 1 of 4	1		ENSP00000416386.2
CHRNB4	ENST00000559849.5	n.47-949T>C		intron_variant	Intron 7 of 11	1		ENSP00000457404.1
CHRNB4	ENST00000560511.5	n.410-949T>C		intron_variant	Intron 4 of 6	3

Frequencies

GnomAD3 genomes AF: 0.625 AC: 94738 AN: 151486 Hom.: 32581 Cov.: 30

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.715

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.638

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.625 AC: 94770 AN: 151594 Hom.: 32584 Cov.: 30 AF XY: 0.617 AC XY: 45701 AN XY: 74048

African (AFR) AF: 0.387 AC: 15929 AN: 41192

American (AMR) AF: 0.530 AC: 8059 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 2692 AN: 3468

East Asian (EAS) AF: 0.210 AC: 1079 AN: 5126

South Asian (SAS) AF: 0.535 AC: 2570 AN: 4800

European-Finnish (FIN) AF: 0.715 AC: 7522 AN: 10524

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.805 AC: 54720 AN: 67950

Other (OTH) AF: 0.632 AC: 1332 AN: 2108

Alfa AF: 0.721 Hom.: 14607

Bravo AF: 0.593

Asia WGS AF: 0.369 AC: 1285 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.1
DANN	Benign	0.65
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11636605; hg19: chr15-78928878;