15-78637136-T-G

Variant names:

• chr15-78637136-T-G
• rs11072768
• NM_000750.5:c.56-1549A>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.56-1549A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.624 in 152,048 control chromosomes in the GnomAD database, including 32,598 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 0.62 (32598 hom., cov: 31)
• Consequence: CHRNB4 NM_000750.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.967
• Publications: 24 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=-0.88).
• 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.56-1549A>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.56-1549A>C		intron_variant	Intron 1 of 5	1	NM_000750.5	ENSP00000261751.3
CHRNB4	ENST00000412074.6	c.56-1549A>C		intron_variant	Intron 1 of 4	1		ENSP00000416386.2
CHRNB4	ENST00000559849.5	n.47-1549A>C		intron_variant	Intron 7 of 11	1		ENSP00000457404.1
CHRNB4	ENST00000560511.5	n.410-1549A>C		intron_variant	Intron 4 of 6	3

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94820 AN: 151930 Hom.: 32594 Cov.: 31

Gnomad AFR AF: 0.384

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.776

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.636

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

GnomAD4 genome AF: 0.624 AC: 94853 AN: 152048 Hom.: 32598 Cov.: 31 AF XY: 0.615 AC XY: 45749 AN XY: 74330

African (AFR) AF: 0.384 AC: 15934 AN: 41452

American (AMR) AF: 0.529 AC: 8076 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.776 AC: 2694 AN: 3470

East Asian (EAS) AF: 0.212 AC: 1094 AN: 5168

South Asian (SAS) AF: 0.534 AC: 2574 AN: 4820

European-Finnish (FIN) AF: 0.714 AC: 7552 AN: 10574

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

European-Non Finnish (NFE) AF: 0.805 AC: 54736 AN: 67976

Other (OTH) AF: 0.629 AC: 1328 AN: 2112

Alfa AF: 0.710 Hom.: 16796

Bravo AF: 0.592

Asia WGS AF: 0.370 AC: 1289 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.79
DANN	Benign	0.78
PhyloP100		-0.97
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: rs11072768; hg19: chr15-78929478; COSMIC: COSV55718916;