rs2071057

Variant names:

• chr12-6840888-G-A
• rs2071057
• ENST00000541978.5:c.-176G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000541978.5(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 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.149
• Publications: 3 publications found

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]

GNB3 Gene-Disease associations (from GenCC):

• congenital stationary night blindness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital stationary night blindness 1H

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000541978.5. 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
	GNB3	NM_002075.4	MANE Select	c.-176G>A		upstream_gene	N/A	NP_002066.1
	GNB3	NM_001297571.2		c.-176G>A		upstream_gene	N/A	NP_001284500.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB3	ENST00000541978.5	TSL:2	c.-176G>A		5_prime_UTR	Exon 1 of 8	ENSP00000439753.2
	GNB3	ENST00000675241.1		c.-176G>A		5_prime_UTR	Exon 2 of 5	ENSP00000501677.1
	GNB3	ENST00000541257.5	TSL:5	c.-30-370G>A		intron	N/A	ENSP00000442002.1

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

African (AFR) AF: 0.00467 AC: 2 AN: 428

American (AMR) AF: 0.110 AC: 104 AN: 944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 654

East Asian (EAS) AF: 0.173 AC: 132 AN: 762

South Asian (SAS) AF: 0.00438 AC: 13 AN: 2968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 112

European-Non Finnish (NFE) AF: 0.000410 AC: 6 AN: 14642

Other (OTH) AF: 0.0101 AC: 13 AN: 1286

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

African (AFR) AF: 0.00196 AC: 78 AN: 39872

American (AMR) AF: 0.0696 AC: 1013 AN: 14558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.172 AC: 831 AN: 4832

South Asian (SAS) AF: 0.0106 AC: 48 AN: 4544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.000358 AC: 24 AN: 66950

Other (OTH) AF: 0.0182 AC: 37 AN: 2038

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.9
DANN	Benign	0.82
PhyloP100		0.15
PromoterAI		0.030	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2071057; hg19: chr12-6950052;