12-6841291-G-A

Variant names:

• chr12-6841291-G-A
• NM_002075.4:c.4G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002075.4(GNB3):​c.4G>A​(p.Gly2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNB3 NM_002075.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB3	NM_002075.4	c.4G>A	p.Gly2Arg	missense_variant	Exon 2 of 10	ENST00000229264.8	NP_002066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB3	ENST00000229264.8	c.4G>A	p.Gly2Arg	missense_variant	Exon 2 of 10	5	NM_002075.4	ENSP00000229264.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. This variant has not been reported in the literature in individuals affected with GNB3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2 of the GNB3 protein (p.Gly2Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;.;T;.;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.2	L;.;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.80	N;N;N;N;N
REVEL	Benign	0.19
Sift	Uncertain	0.011	D;D;D;D;D
Sift4G	Uncertain	0.046	D;D;D;D;D
Polyphen		0.16	B;.;.;P;.
Vest4		0.41
MutPred		0.34		Gain of MoRF binding (P = 0.033);Gain of MoRF binding (P = 0.033);Gain of MoRF binding (P = 0.033);Gain of MoRF binding (P = 0.033);Gain of MoRF binding (P = 0.033);
MVP		0.62
MPC		0.48
ClinPred		0.87	D
GERP RS		4.8
Varity_R		0.32
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-6950455;