rs12900519

Positions:

• chr15-78656785-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000559849.5(CHRNB4):​c.-708-95G>A variant causes a intron, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.88 in 152,156 control chromosomes in the GnomAD database, including 59,172 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 0.88 (59172 hom., cov: 31)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: CHRNB4 ENST00000559849.5 intron, NMD_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.230

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB4	XM_011521186.3	c.-229-1122G>A		intron_variant
CHRNB4	XM_011521187.3	c.-135-1122G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB4	ENST00000559849.5	c.-708-95G>A		intron_variant, NMD_transcript_variant		1
CHRNB4	ENST00000560511.5	n.229-1122G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.880 AC: 133809 AN: 152032 Hom.: 59146 Cov.: 31

Gnomad AFR AF: 0.811

Gnomad AMI AF: 0.942

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.916

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.925

Gnomad FIN AF: 0.862

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.929

Gnomad OTH AF: 0.886

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 0 AF XY: 0.500 AC XY: 2 AN XY: 4

Gnomad4 AFR exome AF: 0.500

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.880 AC: 133895 AN: 152152 Hom.: 59172 Cov.: 31 AF XY: 0.877 AC XY: 65205 AN XY: 74388

Gnomad4 AFR AF: 0.811

Gnomad4 AMR AF: 0.870

Gnomad4 ASJ AF: 0.916

Gnomad4 EAS AF: 0.772

Gnomad4 SAS AF: 0.925

Gnomad4 FIN AF: 0.862

Gnomad4 NFE AF: 0.929

Gnomad4 OTH AF: 0.884

Alfa AF: 0.921 Hom.: 83670

Bravo AF: 0.877

Asia WGS AF: 0.828 AC: 2882 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.8
DANN	Benign	0.30

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12900519; hg19: chr15-78949127;