12-6845648-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002075.4(GNB3):c.762C>T(p.Asp254=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,613,990 control chromosomes in the GnomAD database, including 415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (64 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (351 hom.)
• Consequence: GNB3 NM_002075.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.74

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-6845648-C-T is Benign according to our data. Variant chr12-6845648-C-T is described in ClinVar as [Benign]. Clinvar id is 1169656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB3	NM_002075.4	c.762C>T	p.Asp254=	synonymous_variant	9/10	ENST00000229264.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB3	ENST00000229264.8	c.762C>T	p.Asp254=	synonymous_variant	9/10	5	NM_002075.4	P1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1703 AN: 152206 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00799

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0698

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.0414

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0186

GnomAD3 exomes AF: 0.0198 AC: 4976 AN: 251200 Hom.: 274 AF XY: 0.0151 AC XY: 2051 AN XY: 135850

Gnomad AFR exome AF: 0.00800

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.0369

Gnomad SAS exome AF: 0.00300

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.00509 AC: 7437 AN: 1461666 Hom.: 351 Cov.: 31 AF XY: 0.00450 AC XY: 3270 AN XY: 727156

Gnomad4 AFR exome AF: 0.00762

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0392

Gnomad4 SAS exome AF: 0.00314

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00576

GnomAD4 genome AF: 0.0113 AC: 1714 AN: 152324 Hom.: 64 Cov.: 32 AF XY: 0.0124 AC XY: 925 AN XY: 74484

Gnomad4 AFR AF: 0.00806

Gnomad4 AMR AF: 0.0703

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.0413

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.00316 Hom.: 4

Bravo AF: 0.0172

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

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	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	13
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2234757; hg19: chr12-6954812; COSMIC: COSV57529887; COSMIC: COSV57529887;