chr12-6847298-C-T

Variant names:

• chr12-6847298-C-T
• rs5446
• NM_002075.4:c.*400C>T

Variant summary

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

The NM_002075.4(GNB3):​c.*400C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 220,912 control chromosomes in the GnomAD database, including 11,406 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 0.33 (8442 hom., cov: 32)
  • Exomes 𝑓: 0.28 (2964 hom.)
• Consequence: GNB3 NM_002075.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0190
• Publications: 51 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]

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB3	NM_002075.4	c.*400C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000229264.8	NP_002066.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB3	ENST00000229264.8	c.*400C>T		3_prime_UTR_variant	Exon 10 of 10	5	NM_002075.4	ENSP00000229264.3

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49539 AN: 152052 Hom.: 8432 Cov.: 32

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.343

GnomAD4 exome AF: 0.280 AC: 19263 AN: 68742 Hom.: 2964 Cov.: 0 AF XY: 0.279 AC XY: 9875 AN XY: 35448

African (AFR) AF: 0.419 AC: 1041 AN: 2486

American (AMR) AF: 0.238 AC: 910 AN: 3818

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 747 AN: 2504

East Asian (EAS) AF: 0.172 AC: 931 AN: 5408

South Asian (SAS) AF: 0.296 AC: 781 AN: 2638

European-Finnish (FIN) AF: 0.244 AC: 1230 AN: 5044

Middle Eastern (MID) AF: 0.362 AC: 113 AN: 312

European-Non Finnish (NFE) AF: 0.289 AC: 12233 AN: 42330

Other (OTH) AF: 0.304 AC: 1277 AN: 4202

GnomAD4 genome AF: 0.326 AC: 49573 AN: 152170 Hom.: 8442 Cov.: 32 AF XY: 0.321 AC XY: 23917 AN XY: 74402

African (AFR) AF: 0.424 AC: 17581 AN: 41506

American (AMR) AF: 0.295 AC: 4503 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1105 AN: 3472

East Asian (EAS) AF: 0.210 AC: 1087 AN: 5178

South Asian (SAS) AF: 0.298 AC: 1441 AN: 4830

European-Finnish (FIN) AF: 0.245 AC: 2601 AN: 10602

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20073 AN: 67980

Other (OTH) AF: 0.346 AC: 731 AN: 2114

Alfa AF: 0.310 Hom.: 10885

Bravo AF: 0.333

Asia WGS AF: 0.293 AC: 1016 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.3
DANN	Benign	0.69
PhyloP100		-0.019
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5446; hg19: chr12-6956462; COSMIC: COSV57529935; COSMIC: COSV57529935;