15-78631645-C-T

Variant names:

• chr15-78631645-C-T
• rs17487223
• NM_000750.5:c.205-313G>A

Variant summary

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

The NM_000750.5(CHRNB4):​c.205-313G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 152,136 control chromosomes in the GnomAD database, including 6,771 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 0.27 (6771 hom., cov: 32)
• Consequence: CHRNB4 NM_000750.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.346
• Publications: 40 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

ENSG00000259555 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000750.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB4	NM_000750.5	MANE Select	c.205-313G>A		intron	N/A	NP_000741.1
	CHRNB4	NM_001256567.3		c.205-313G>A		intron	N/A	NP_001243496.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB4	ENST00000261751.8	TSL:1 MANE Select	c.205-313G>A		intron	N/A	ENSP00000261751.3
	CHRNB4	ENST00000412074.6	TSL:1	c.205-313G>A		intron	N/A	ENSP00000416386.2
	CHRNB4	ENST00000559849.5	TSL:1	n.*113-313G>A		intron	N/A	ENSP00000457404.1

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41226 AN: 152016 Hom.: 6769 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.270

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.0302

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.303

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

GnomAD4 genome AF: 0.271 AC: 41250 AN: 152136 Hom.: 6771 Cov.: 32 AF XY: 0.269 AC XY: 20020 AN XY: 74372

African (AFR) AF: 0.111 AC: 4607 AN: 41516

American (AMR) AF: 0.270 AC: 4131 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1412 AN: 3470

East Asian (EAS) AF: 0.0304 AC: 158 AN: 5190

South Asian (SAS) AF: 0.226 AC: 1091 AN: 4818

European-Finnish (FIN) AF: 0.358 AC: 3792 AN: 10600

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24912 AN: 67946

Other (OTH) AF: 0.300 AC: 634 AN: 2114

Alfa AF: 0.321 Hom.: 6000

Bravo AF: 0.255

Asia WGS AF: 0.126 AC: 442 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.98
DANN	Benign	0.44
PhyloP100		-0.35
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: rs17487223; hg19: chr15-78923987;