rs1948

Variant names:

• chr15-78625057-A-G
• rs1948
• ENST00000412074.6:c.594T>C
• CHRNB4 p.Ala198Ala

Your query was ambiguous. Multiple possible variants found:

• chr15-78625057-A-G
• chr15-78625057-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001256567.3(CHRNB4):​c.594T>C​(p.Ala198Ala) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A198A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.70 (37855 hom., cov: 33)
  • Exomes 𝑓: 0.66 (323365 hom.)
• Consequence: CHRNB4 NM_001256567.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.921
• Publications: 91 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 -21 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 VariationId is 1289303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256567.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB4	NM_000750.5	MANE Select	c.*76T>C		3_prime_UTR	Exon 6 of 6	NP_000741.1	P30926-1
	CHRNB4	NM_001256567.3		c.594T>C	p.Ala198Ala	synonymous	Exon 5 of 5	NP_001243496.1	P30926-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB4	ENST00000412074.6	TSL:1	c.594T>C	p.Ala198Ala	synonymous	Exon 5 of 5	ENSP00000416386.2	P30926-2
	CHRNB4	ENST00000261751.8	TSL:1 MANE Select	c.*76T>C		3_prime_UTR	Exon 6 of 6	ENSP00000261751.3	P30926-1
	CHRNB4	ENST00000929174.1		c.*76T>C		3_prime_UTR	Exon 7 of 7	ENSP00000599233.1

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

GnomAD2 exomes AF: 0.694 AC: 169878 AN: 244840 AF XY: 0.689

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 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

African (AFR) AF: 0.782 AC: 26177 AN: 33478

American (AMR) AF: 0.851 AC: 38072 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 17651 AN: 26132

East Asian (EAS) AF: 0.558 AC: 22137 AN: 39690

South Asian (SAS) AF: 0.697 AC: 60108 AN: 86240

European-Finnish (FIN) AF: 0.669 AC: 32717 AN: 48918

Middle Eastern (MID) AF: 0.723 AC: 4165 AN: 5764

European-Non Finnish (NFE) AF: 0.653 AC: 726401 AN: 1111760

Other (OTH) AF: 0.665 AC: 40101 AN: 60338

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

African (AFR) AF: 0.778 AC: 32274 AN: 41488

American (AMR) AF: 0.786 AC: 12025 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2329 AN: 3464

East Asian (EAS) AF: 0.529 AC: 2738 AN: 5172

South Asian (SAS) AF: 0.686 AC: 3313 AN: 4826

European-Finnish (FIN) AF: 0.670 AC: 7070 AN: 10558

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44804 AN: 67950

Other (OTH) AF: 0.711 AC: 1501 AN: 2112

Alfa AF: 0.675 Hom.: 57366

Bravo AF: 0.714

Asia WGS AF: 0.654 AC: 2278 AN: 3478

EpiCase AF: 0.675

EpiControl AF: 0.669

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.98
DANN	Benign	0.46
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1948;

hg19: chr15-78917399;

COSMIC: COSV55716391;

COSMIC: COSV55716391;