NM_002075.4:c.41T>G

Variant names:

• chr12-6841328-T-G
• rs782520640
• NM_002075.4:c.41T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002075.4(GNB3):​c.41T>G​(p.Leu14Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GNB3 NM_002075.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.67
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.41T>G	p.Leu14Arg	missense	Exon 2 of 10	NP_002066.1	P16520-1
	GNB3	NM_001297571.2		c.41T>G	p.Leu14Arg	missense	Exon 2 of 10	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.41T>G	p.Leu14Arg	missense	Exon 2 of 10	ENSP00000229264.3	P16520-1
	GNB3	ENST00000435982.6	TSL:1	c.41T>G	p.Leu14Arg	missense	Exon 2 of 10	ENSP00000414734.2	E9PCP0
	GNB3	ENST00000542868.1	TSL:1	n.288T>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249280 AF XY: 0.00000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461222 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726830

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111708

Other (OTH) AF: 0.00 AC: 0 AN: 60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.39		Loss of ubiquitination at K16 (P = 0.0184)
MVP		0.53
MPC		1.0
ClinPred		0.99	D
GERP RS		4.8
PromoterAI		0.039	Neutral
Varity_R		0.86
gMVP		0.78
Mutation Taster		=39/61	disease causing

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: rs782520640; hg19: chr12-6950492;