1-1806512-C-T

Position:

• chr1-1806512-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_002074.5(GNB1):​c.230G>A​(p.Gly77Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G77A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNB1 NM_002074.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.71

Genes affected

GNB1 (HGNC:4396): (G protein subunit beta 1) 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. Beta subunits are important regulators of alpha subunits, as well as of certain signal transduction receptors and effectors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-1806512-C-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GNB1. . Gene score misZ 3.8328 (greater than the threshold 3.09). Trascript score misZ 3.4817 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 42.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913
• PP5: Variant 1-1806512-C-T is Pathogenic according to our data. Variant chr1-1806512-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 985590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNB1	NM_002074.5	c.230G>A	p.Gly77Asp	missense_variant	6/12	ENST00000378609.9	NP_002065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNB1	ENST00000378609.9	c.230G>A	p.Gly77Asp	missense_variant	6/12	1	NM_002074.5	ENSP00000367872	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 42 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	-	- Variant is absent from gnomAD (both v2 and v3). - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Four other missense variants have been reported in at least nine probands with neurodevelopmental delay and reported de novo where inheritance information were provided (ClinVar, DECIPHER, PMID: 27108799, 29174093, 30194818). - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least two probands, one of whom was reported to be de novo (ClinVar). - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). Additional information: - Loss of function is a known mechanism of disease in this gene and is associated with intellectual disability, autosomal dominant 42 (MIM#616973). - This gene is associated with autosomal dominant disease. - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. - This variant is heterozygous. - An alternative amino acid change at the same position has been observed in gnomAD (v3: 1 heterozygote, 0 homozygotes). - Missense variant with conflicting in silico predictions and uninformative conservation. - No published segregation evidence has been identified for this variant. - No published functional evidence has been identified for this variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 29, 2023	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.230G>A (p.G77D) alteration is located in exon 6 (coding exon 4) of the GNB1 gene. This alteration results from a G to A substitution at nucleotide position 230, causing the glycine (G) at amino acid position 77 to be replaced by an aspartic acid (D). The alteration is not observed in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GNB1 c.230G>A alteration was not observed, with coverage at this position. Alterations at the same codon has been observed in affected individuals:_x000D_ _x000D_ Several alterations have been described at the same codon to occur de novo in patients with a neurodevelopmental phenotype, including p.G77S, p.G77V, p.G77R, and p.G77A. All patients present with global developmental delay and hypotonia, while additional features have been reported in some including congenital defects, dystonia, eye abnormalities, acute lymphoblastic leukemia, and cutaneous mastocystosis (Brett, 2017; Hemati, 2018; Petrovski, 2016; Szcaluba, 2018). Additionally, de novo changes in neighboring amino acid residues (p.D76 and p.K78) have been reported in three additional individuals with global developmental delay, hypotonia, and epilepsy (Petrovski, 2016). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.G77 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.G77 amino acid is located in a WD40 repeat region in the amino-terminal interface of GNB1. Crystal structures of heterotrimeric G-alpha-beta-gamma have demonstrated that this is a region of interaction between the G-protein beta subunit and alpha subunit (Ford, 1998). The adjacent p.K78 residue is reported to play an important role in regulating activation of adenylyl cyclase 2, inhibition of calcium channels, and activation of potassium channels (Ford, 1998; Petrovski, 2016). The alteration is predicted deleterious by in silico models:_x000D_ _x000D_ The p.G77D alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Intellectual disability Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Feb 25, 2021

The variant chr1-1737951-C-T, GNB1(NM_002074.5):c.230G>A,p.(Gly77Asp) was identified in an individual with NDD. Inheritance was de novo (heterozygous). The variant was reviewed according to current ACMG recommendations and classified as Likely Pathogenic (criteria: PS2_Moderate, PS4_Supporting, PM2_Supporting, PM5_Moderate, PP2_Supporting, PP3_Supporting). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Benign	0.97
DEOGEN2	Uncertain	0.45	T;T;T;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Uncertain	2.3	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.1	.;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;.;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.97
MutPred		0.75		Gain of ubiquitination at K78 (P = 0.1079);Gain of ubiquitination at K78 (P = 0.1079);.;Gain of ubiquitination at K78 (P = 0.1079);Gain of ubiquitination at K78 (P = 0.1079);
MVP		0.95
MPC		3.5
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.88

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

Publications

LitVar

Other links and lift over

dbSNP: rs1135401746; hg19: chr1-1737951;