ENST00000559849.5:n.-429A>C

Variant names:

• chr15-78660961-A-G
• XM_011521186.3:c.-769T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The XM_011521186.3(CHRNB4):​c.-769T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000353 in 283,016 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CHRNB4 XM_011521186.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.702
• Publications: 0 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]

ENSG00000290426 (HGNC:):

RPL18P11 (HGNC:35742): (ribosomal protein L18 pseudogene 11)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB4	XM_011521186.3	c.-769T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 10		XP_011519488.1
CHRNB4	XM_011521187.3	c.-675T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 9		XP_011519489.1
CHRNB4	XM_011521186.3	c.-769T>C		5_prime_UTR_variant	Exon 1 of 10		XP_011519488.1
CHRNB4	XM_011521187.3	c.-675T>C		5_prime_UTR_variant	Exon 1 of 9		XP_011519489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB4	ENST00000560511.5	n.229-5298T>C		intron_variant	Intron 2 of 6	3
ENSG00000290426	ENST00000569846.2	n.226+92A>G		intron_variant	Intron 1 of 5	4
ENSG00000290426	ENST00000846725.1	n.-174A>G		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000353 AC: 1 AN: 283016 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 157082

African (AFR) AF: 0.00 AC: 0 AN: 7882

American (AMR) AF: 0.00 AC: 0 AN: 16488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6972

East Asian (EAS) AF: 0.00 AC: 0 AN: 13768

South Asian (SAS) AF: 0.0000214 AC: 1 AN: 46794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 962

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 161262

Other (OTH) AF: 0.00 AC: 0 AN: 14568

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.29
DANN	Benign	0.57
PhyloP100		-0.70

Splicing

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

Other links and lift over

hg19: chr15-78953303;