rs2301339

chr12-6845460-G-Achr12-6845460-G-Cchr12-6845460-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002075.4(GNB3):c.700-126G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 656,438 control chromosomes in the GnomAD database, including 48,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (17343 hom., cov: 32)
  • Exomes 𝑓: 0.34 (31211 hom.)
• Consequence: GNB3 NM_002075.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.452

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]

CDCA3 (HGNC:14624): (cell division cycle associated 3) Predicted to be involved in cell division and protein ubiquitination. Located in adherens junction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-6845460-G-A is Benign according to our data. Variant chr12-6845460-G-A is described in ClinVar as [Benign]. Clinvar id is 675808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB3	NM_002075.4	c.700-126G>A		intron_variant		ENST00000229264.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB3	ENST00000229264.8	c.700-126G>A		intron_variant		5	NM_002075.4	P1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66597 AN: 151990 Hom.: 17312 Cov.: 32

Gnomad AFR AF: 0.735

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.507

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.305

Gnomad OTH AF: 0.443

GnomAD4 exome AF: 0.336 AC: 169536 AN: 504332 Hom.: 31211 Cov.: 6 AF XY: 0.333 AC XY: 88590 AN XY: 266230

Gnomad4 AFR exome AF: 0.746

Gnomad4 AMR exome AF: 0.349

Gnomad4 ASJ exome AF: 0.318

Gnomad4 EAS exome AF: 0.509

Gnomad4 SAS exome AF: 0.318

Gnomad4 FIN exome AF: 0.265

Gnomad4 NFE exome AF: 0.305

Gnomad4 OTH exome AF: 0.366

GnomAD4 genome AF: 0.438 AC: 66687 AN: 152106 Hom.: 17343 Cov.: 32 AF XY: 0.434 AC XY: 32257 AN XY: 74340

Gnomad4 AFR AF: 0.735

Gnomad4 AMR AF: 0.401

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.507

Gnomad4 SAS AF: 0.315

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.305

Gnomad4 OTH AF: 0.447

Alfa AF: 0.309 Hom.: 4704

Bravo AF: 0.466

Asia WGS AF: 0.416 AC: 1446 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.78
Dann	Benign	0.68

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: rs2301339; hg19: chr12-6954624;