dbSNP rs2071057: GNB3:n.935G>A (chr12-6840888-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000540458.5(GNB3):n.935G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 169,852 control chromosomes in the GnomAD database, including 146 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 0.014 ( 129 hom., cov: 31)

Exomes 𝑓: 0.012 ( 17 hom. )

Consequence

GNB3
ENST00000540458.5 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.149

Publications

3 publications found

Variant links:

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

GNB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNB3	NM_002075.4 link	c.-176G>A		upstream_gene_variant		ENST00000229264.8	NP_002066.1	P16520-1F1T0G5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB3	ENST00000229264.8 link	c.-176G>A		upstream_gene_variant		5	NM_002075.4	ENSP00000229264.3		P16520-1

Frequencies

GnomAD3 genomes

AF:

0.0138

AC:

2024

AN:

146768

Hom.:

127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0691

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.172

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000358

Gnomad OTH

AF:

0.0184

GnomAD4 exome

AF:

0.0118

AC:

270

AN:

22952

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

132

AN XY:

12656

show subpopulations

African (AFR)

AF:

0.00467

AC:

AN:

428

American (AMR)

AF:

0.110

AC:

104

AN:

944

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

654

East Asian (EAS)

AF:

0.173

AC:

132

AN:

762

South Asian (SAS)

AF:

0.00438

AC:

AN:

2968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

112

European-Non Finnish (NFE)

AF:

0.000410

AC:

AN:

14642

Other (OTH)

AF:

0.0101

AC:

AN:

1286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0138

AC:

2031

AN:

146900

Hom.:

129

Cov.:

AF XY:

0.0158

AC XY:

1126

AN XY:

71408

show subpopulations

African (AFR)

AF:

0.00196

AC:

AN:

39872

American (AMR)

AF:

0.0696

AC:

1013

AN:

14558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3420

East Asian (EAS)

AF:

0.172

AC:

831

AN:

4832

South Asian (SAS)

AF:

0.0106

AC:

AN:

4544

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.000358

AC:

AN:

66950

Other (OTH)

AF:

0.0182

AC:

AN:

2038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

171

256

342

427

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00804

Hom.:

Bravo

AF:

0.0196

Asia WGS

AF:

0.0460

AC:

160

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.9

(source)

DANN

Benign

0.82

PhyloP100

0.15

PromoterAI

0.030

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over