chr15-78633676-T-C

Variant names:

• chr15-78633676-T-C
• rs950776
• NM_000750.5:c.204+1763A>G

Variant summary

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

The NM_000750.5(CHRNB4):​c.204+1763A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,068 control chromosomes in the GnomAD database, including 5,785 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 0.26 (5785 hom., cov: 31)
• Consequence: CHRNB4 NM_000750.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.126
• Publications: 52 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

ENSG00000259555 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	NM_000750.5	c.204+1763A>G		intron_variant	Intron 2 of 5	ENST00000261751.8	NP_000741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB4	ENST00000261751.8	c.204+1763A>G		intron_variant	Intron 2 of 5	1	NM_000750.5	ENSP00000261751.3

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38949 AN: 151950 Hom.: 5790 Cov.: 31

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.256 AC: 38938 AN: 152068 Hom.: 5785 Cov.: 31 AF XY: 0.255 AC XY: 18968 AN XY: 74348

African (AFR) AF: 0.114 AC: 4718 AN: 41488

American (AMR) AF: 0.198 AC: 3025 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1095 AN: 3470

East Asian (EAS) AF: 0.136 AC: 705 AN: 5170

South Asian (SAS) AF: 0.295 AC: 1423 AN: 4818

European-Finnish (FIN) AF: 0.327 AC: 3454 AN: 10574

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23571 AN: 67960

Other (OTH) AF: 0.248 AC: 523 AN: 2112

Alfa AF: 0.316 Hom.: 33878

Bravo AF: 0.238

Asia WGS AF: 0.204 AC: 709 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.0
DANN	Benign	0.45
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs950776; hg19: chr15-78926018;