15-78625057-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The ENST00000412074.6(CHRNB4):c.594T>C(p.Ala198=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 1,609,104 control chromosomes in the GnomAD database, including 361,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.70 (37855 hom., cov: 33)
  • Exomes 𝑓: 0.66 (323365 hom.)
• Consequence: CHRNB4 ENST00000412074.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.921

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-78625057-A-G is Benign according to our data. Variant chr15-78625057-A-G is described in ClinVar as [Benign]. Clinvar id is 1289303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.921 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB4	NM_000750.5	c.*76T>C		3_prime_UTR_variant	6/6	ENST00000261751.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB4	ENST00000412074.6	c.594T>C	p.Ala198=	synonymous_variant	5/5	1
CHRNB4	ENST00000261751.8	c.*76T>C		3_prime_UTR_variant	6/6	1	NM_000750.5	P1

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106744 AN: 151950 Hom.: 37800 Cov.: 33

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.627

Gnomad AMR AF: 0.786

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.530

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.706

GnomAD3 exomes AF: 0.694 AC: 169878 AN: 244840 Hom.: 59992 AF XY: 0.689 AC XY: 91630 AN XY: 132966

Gnomad AFR exome AF: 0.782

Gnomad AMR exome AF: 0.861

Gnomad ASJ exome AF: 0.686

Gnomad EAS exome AF: 0.523

Gnomad SAS exome AF: 0.705

Gnomad FIN exome AF: 0.671

Gnomad NFE exome AF: 0.659

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.664 AC: 967529 AN: 1457036 Hom.: 323365 Cov.: 68 AF XY: 0.664 AC XY: 481318 AN XY: 724976

Gnomad4 AFR exome AF: 0.782

Gnomad4 AMR exome AF: 0.851

Gnomad4 ASJ exome AF: 0.675

Gnomad4 EAS exome AF: 0.558

Gnomad4 SAS exome AF: 0.697

Gnomad4 FIN exome AF: 0.669

Gnomad4 NFE exome AF: 0.653

Gnomad4 OTH exome AF: 0.665

GnomAD4 genome AF: 0.703 AC: 106854 AN: 152068 Hom.: 37855 Cov.: 33 AF XY: 0.703 AC XY: 52240 AN XY: 74320

Gnomad4 AFR AF: 0.778

Gnomad4 AMR AF: 0.786

Gnomad4 ASJ AF: 0.672

Gnomad4 EAS AF: 0.529

Gnomad4 SAS AF: 0.686

Gnomad4 FIN AF: 0.670

Gnomad4 NFE AF: 0.659

Gnomad4 OTH AF: 0.711

Alfa AF: 0.669 Hom.: 44810

Bravo AF: 0.714

Asia WGS AF: 0.654 AC: 2278 AN: 3478

EpiCase AF: 0.675

EpiControl AF: 0.669

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 27, 2020

This variant is associated with the following publications: (PMID: 23691088) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.98
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1948; hg19: chr15-78917399; COSMIC: COSV55716391; COSMIC: COSV55716391;