rs12594550

Variant names:

• chr15-78666695-C-G
• rs12594550
• ENST00000560511.5:n.229-11032G>C

Variant summary

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

The ENST00000560511.5(CHRNB4):​n.229-11032G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 152,082 control chromosomes in the GnomAD database, including 2,724 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 0.17 (2724 hom., cov: 32)
• Consequence: CHRNB4 ENST00000560511.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 9 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

ENSG00000290426 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB4	ENST00000560511.5	n.229-11032G>C		intron_variant	Intron 2 of 6	3
ENSG00000290426	ENST00000569846.2	n.366+5161C>G		intron_variant	Intron 2 of 5	4
ENSG00000290426	ENST00000846725.1	n.400+5161C>G		intron_variant	Intron 1 of 5

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26538 AN: 151962 Hom.: 2719 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.175 AC: 26557 AN: 152082 Hom.: 2724 Cov.: 32 AF XY: 0.181 AC XY: 13489 AN XY: 74326

African (AFR) AF: 0.122 AC: 5074 AN: 41502

American (AMR) AF: 0.320 AC: 4881 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 509 AN: 3466

East Asian (EAS) AF: 0.203 AC: 1046 AN: 5164

South Asian (SAS) AF: 0.370 AC: 1781 AN: 4816

European-Finnish (FIN) AF: 0.203 AC: 2147 AN: 10574

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10429 AN: 67996

Other (OTH) AF: 0.189 AC: 400 AN: 2112

Alfa AF: 0.168 Hom.: 295

Bravo AF: 0.181

Asia WGS AF: 0.319 AC: 1107 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.34
DANN	Benign	0.45
PhyloP100		-1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12594550; hg19: chr15-78959037;