chr12-6841239-G-A

Variant names:

• chr12-6841239-G-A
• rs28395781
• NM_002075.4:c.-30-19G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002075.4(GNB3):​c.-30-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0684 in 1,512,448 control chromosomes in the GnomAD database, including 4,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (320 hom., cov: 32)
  • Exomes 𝑓: 0.070 (3725 hom.)
• Consequence: GNB3 NM_002075.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.449
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-6841239-G-A is Benign according to our data. Variant chr12-6841239-G-A is described in ClinVar as Benign. ClinVar VariationId is 1257613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.073 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002075.4. 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.-30-19G>A		intron	N/A	NP_002066.1	P16520-1
	GNB3	NM_001297571.2		c.-30-19G>A		intron	N/A	NP_001284500.1	E9PCP0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNB3	ENST00000229264.8	TSL:5 MANE Select	c.-30-19G>A		intron	N/A	ENSP00000229264.3	P16520-1
	GNB3	ENST00000435982.6	TSL:1	c.-30-19G>A		intron	N/A	ENSP00000414734.2	E9PCP0
	GNB3	ENST00000542868.1	TSL:1	n.199G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0530 AC: 8034 AN: 151660 Hom.: 320 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0747

Gnomad OTH AF: 0.0436

GnomAD2 exomes AF: 0.0542 AC: 12085 AN: 222928 AF XY: 0.0550

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.0255

Gnomad ASJ exome AF: 0.0330

Gnomad EAS exome AF: 0.0000595

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.0755

Gnomad OTH exome AF: 0.0544

GnomAD4 exome AF: 0.0701 AC: 95389 AN: 1360668 Hom.: 3725 Cov.: 23 AF XY: 0.0686 AC XY: 46591 AN XY: 679468

African (AFR) AF: 0.0101 AC: 312 AN: 30896

American (AMR) AF: 0.0285 AC: 1194 AN: 41846

Ashkenazi Jewish (ASJ) AF: 0.0356 AC: 865 AN: 24304

East Asian (EAS) AF: 0.0000273 AC: 1 AN: 36646

South Asian (SAS) AF: 0.0200 AC: 1645 AN: 82066

European-Finnish (FIN) AF: 0.130 AC: 6505 AN: 50178

Middle Eastern (MID) AF: 0.0294 AC: 160 AN: 5434

European-Non Finnish (NFE) AF: 0.0789 AC: 81481 AN: 1033236

Other (OTH) AF: 0.0575 AC: 3226 AN: 56062

GnomAD4 genome AF: 0.0529 AC: 8032 AN: 151780 Hom.: 320 Cov.: 32 AF XY: 0.0545 AC XY: 4042 AN XY: 74194

African (AFR) AF: 0.0120 AC: 497 AN: 41446

American (AMR) AF: 0.0491 AC: 749 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3470

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5100

South Asian (SAS) AF: 0.0162 AC: 76 AN: 4698

European-Finnish (FIN) AF: 0.134 AC: 1414 AN: 10588

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0747 AC: 5074 AN: 67916

Other (OTH) AF: 0.0432 AC: 91 AN: 2108

Alfa AF: 0.0578 Hom.: 65

Bravo AF: 0.0454

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.34
DANN	Benign	0.71
PhyloP100		-0.45
PromoterAI		0.0017	Neutral
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: rs28395781; hg19: chr12-6950403;