chr15-78641976-C-G

Variant names:

• chr15-78641976-C-G
• rs67426328
• ENST00000559849.5:n.47-6389G>C

Variant summary

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

The ENST00000559849.5(CHRNB4):​n.47-6389G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 152,224 control chromosomes in the GnomAD database, including 7,510 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 0.28 (7510 hom., cov: 32)
• Consequence: CHRNB4 ENST00000559849.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.597
• Publications: 10 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 (NFE) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	XM_011521186.3	c.47-6389G>C		intron_variant	Intron 5 of 9		XP_011519488.1
CHRNB4	XM_011521187.3	c.47-6389G>C		intron_variant	Intron 4 of 8		XP_011519489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB4	ENST00000559849.5	n.47-6389G>C		intron_variant	Intron 7 of 11	1		ENSP00000457404.1
CHRNB4	ENST00000560511.5	n.410-6389G>C		intron_variant	Intron 4 of 6	3

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42232 AN: 152106 Hom.: 7506 Cov.: 32

Gnomad AFR AF: 0.0806

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.0276

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.308

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

GnomAD4 genome AF: 0.278 AC: 42245 AN: 152224 Hom.: 7510 Cov.: 32 AF XY: 0.274 AC XY: 20381 AN XY: 74432

African (AFR) AF: 0.0805 AC: 3345 AN: 41568

American (AMR) AF: 0.286 AC: 4374 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1332 AN: 3468

East Asian (EAS) AF: 0.0278 AC: 144 AN: 5178

South Asian (SAS) AF: 0.241 AC: 1164 AN: 4824

European-Finnish (FIN) AF: 0.350 AC: 3710 AN: 10588

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27129 AN: 67990

Other (OTH) AF: 0.304 AC: 644 AN: 2116

Alfa AF: 0.324 Hom.: 1152

Bravo AF: 0.262

Asia WGS AF: 0.122 AC: 429 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.71
PhyloP100		-0.60

Splicing

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

Other links and lift over

dbSNP: rs67426328; hg19: chr15-78934318;