rs2071057

Variant names:

• chr12-6840888-G-A
• rs2071057
• ENST00000541978:c.-176G>A

Variant summary

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

The ENST00000541978(GNB3):​c.-176G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 169,852 control chromosomes in the GnomAD database, including 146 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 0.014 (129 hom., cov: 31)
  • Exomes 𝑓: 0.012 (17 hom.)
• Consequence: GNB3 ENST00000541978 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.149

Genes affected

GNB3 (HGNC:4400): (G protein subunit beta 3) Heterotrimeric guanine nucleotide-binding proteins (G proteins), which integrate signals between receptors and effector proteins, are composed of an alpha, a beta, and a gamma subunit. These subunits are encoded by families of related genes. This gene encodes a beta subunit which belongs to the WD repeat G protein beta family. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. A single-nucleotide polymorphism (C825T) in this gene is associated with essential hypertension and obesity. This polymorphism is also associated with the occurrence of the splice variant GNB3-s, which appears to have increased activity. GNB3-s is an example of alternative splicing caused by a nucleotide change outside of the splice donor and acceptor sites. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB3	NM_002075.4	c.-176G>A		upstream_gene_variant		ENST00000229264.8	NP_002066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB3	ENST00000229264.8	c.-176G>A		upstream_gene_variant		5	NM_002075.4	ENSP00000229264.3

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2024 AN: 146768 Hom.: 127 Cov.: 31

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0691

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000358

Gnomad OTH AF: 0.0184

GnomAD4 exome AF: 0.0118 AC: 270 AN: 22952 Hom.: 17 Cov.: 0 AF XY: 0.0104 AC XY: 132 AN XY: 12656

Gnomad4 AFR exome AF: 0.00467

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.173

Gnomad4 SAS exome AF: 0.00438

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000410

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.0138 AC: 2031 AN: 146900 Hom.: 129 Cov.: 31 AF XY: 0.0158 AC XY: 1126 AN XY: 71408

Gnomad4 AFR AF: 0.00196

Gnomad4 AMR AF: 0.0696

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.172

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000358

Gnomad4 OTH AF: 0.0182

Alfa AF: 0.00804 Hom.: 4

Bravo AF: 0.0196

Asia WGS AF: 0.0460 AC: 160 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.9
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2071057; hg19: chr12-6950052;