rs12441088

Variant names:

• chr15-78635922-G-T
• rs12441088
• NM_000750.5:c.56-335C>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.56-335C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 151,630 control chromosomes in the GnomAD database, including 36,520 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 0.69 (36520 hom., cov: 30)
• Consequence: CHRNB4 NM_000750.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.71
• Publications: 18 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=-1.03).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5	c.56-335C>A		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.56-335C>A		intron_variant	Intron 1 of 5	1	NM_000750.5	ENSP00000261751.3
CHRNB4	ENST00000412074.6	c.56-335C>A		intron_variant	Intron 1 of 4	1		ENSP00000416386.2
CHRNB4	ENST00000559849.5	n.47-335C>A		intron_variant	Intron 7 of 11	1		ENSP00000457404.1
CHRNB4	ENST00000560511.5	n.410-335C>A		intron_variant	Intron 4 of 6	3

Frequencies

GnomAD3 genomes AF: 0.689 AC: 104393 AN: 151512 Hom.: 36509 Cov.: 30

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.677

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.750

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.756

Gnomad OTH AF: 0.680

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

GnomAD4 genome AF: 0.689 AC: 104443 AN: 151630 Hom.: 36520 Cov.: 30 AF XY: 0.681 AC XY: 50429 AN XY: 74068

African (AFR) AF: 0.671 AC: 27702 AN: 41298

American (AMR) AF: 0.542 AC: 8260 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 2599 AN: 3466

East Asian (EAS) AF: 0.527 AC: 2703 AN: 5132

South Asian (SAS) AF: 0.541 AC: 2589 AN: 4784

European-Finnish (FIN) AF: 0.670 AC: 7053 AN: 10528

Middle Eastern (MID) AF: 0.654 AC: 191 AN: 292

European-Non Finnish (NFE) AF: 0.756 AC: 51319 AN: 67870

Other (OTH) AF: 0.671 AC: 1412 AN: 2104

Alfa AF: 0.726 Hom.: 36915

Bravo AF: 0.674

Asia WGS AF: 0.488 AC: 1699 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.71
DANN	Benign	0.30
PhyloP100		-2.7
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: rs12441088; hg19: chr15-78928264; COSMIC: COSV55718945;