rs12441998

Variant names:

• chr15-78637030-G-A
• rs12441998
• NM_000750.5:c.56-1443C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-78637030-G-A
• chr15-78637030-G-T

Variant summary

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

The NM_000750.5(CHRNB4):​c.56-1443C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 152,000 control chromosomes in the GnomAD database, including 32,504 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 (32504 hom., cov: 31)
• Consequence: CHRNB4 NM_000750.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15
• Publications: 25 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=-0.72).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5	c.56-1443C>T		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.56-1443C>T		intron_variant	Intron 1 of 5	1	NM_000750.5	ENSP00000261751.3
CHRNB4	ENST00000412074.6	c.56-1443C>T		intron_variant	Intron 1 of 4	1		ENSP00000416386.2
CHRNB4	ENST00000559849.5	n.47-1443C>T		intron_variant	Intron 7 of 11	1		ENSP00000457404.1
CHRNB4	ENST00000560511.5	n.410-1443C>T		intron_variant	Intron 4 of 6	3

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94696 AN: 151882 Hom.: 32500 Cov.: 31

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.714

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.636

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

GnomAD4 genome AF: 0.623 AC: 94729 AN: 152000 Hom.: 32504 Cov.: 31 AF XY: 0.615 AC XY: 45698 AN XY: 74304

African (AFR) AF: 0.385 AC: 15956 AN: 41442

American (AMR) AF: 0.529 AC: 8078 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 2687 AN: 3468

East Asian (EAS) AF: 0.212 AC: 1098 AN: 5170

South Asian (SAS) AF: 0.534 AC: 2566 AN: 4806

European-Finnish (FIN) AF: 0.714 AC: 7536 AN: 10562

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

European-Non Finnish (NFE) AF: 0.804 AC: 54615 AN: 67964

Other (OTH) AF: 0.628 AC: 1326 AN: 2110

Alfa AF: 0.735 Hom.: 23490

Bravo AF: 0.592

Asia WGS AF: 0.369 AC: 1287 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		1.1
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: rs12441998; hg19: chr15-78929372; COSMIC: COSV55718895;