rs12594247

Variant names:

• chr15-78654291-C-T
• rs12594247
• ENST00000559849.5:n.-110+1253G>A

Variant summary

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

The ENST00000559849.5(CHRNB4):​n.-110+1253G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 152,274 control chromosomes in the GnomAD database, including 2,212 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 0.15 (2212 hom., cov: 32)
• Consequence: CHRNB4 ENST00000559849.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243
• Publications: 14 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000559849.5. 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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB4	ENST00000559849.5	TSL:1	n.-110+1253G>A		intron	N/A	ENSP00000457404.1
	CHRNB4	ENST00000560511.5	TSL:3	n.348+1253G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22266 AN: 152156 Hom.: 2206 Cov.: 32

Gnomad AFR AF: 0.0391

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.154

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

GnomAD4 genome AF: 0.146 AC: 22282 AN: 152274 Hom.: 2212 Cov.: 32 AF XY: 0.153 AC XY: 11393 AN XY: 74442

African (AFR) AF: 0.0391 AC: 1627 AN: 41582

American (AMR) AF: 0.278 AC: 4255 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 505 AN: 3470

East Asian (EAS) AF: 0.210 AC: 1087 AN: 5180

South Asian (SAS) AF: 0.369 AC: 1781 AN: 4822

European-Finnish (FIN) AF: 0.195 AC: 2070 AN: 10606

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

European-Non Finnish (NFE) AF: 0.152 AC: 10356 AN: 68010

Other (OTH) AF: 0.158 AC: 334 AN: 2112

Alfa AF: 0.159 Hom.: 7325

Bravo AF: 0.146

Asia WGS AF: 0.306 AC: 1062 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.2
DANN	Benign	0.53
PhyloP100		0.24

Splicing

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

Other links and lift over

dbSNP: rs12594247; hg19: chr15-78946633;