rs1135401746

Positions:

• chr1-1806512-C-A
• chr1-1806512-C-G
• chr1-1806512-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_002074.5(GNB1):​c.230G>T​(p.Gly77Val) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G77A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GNB1 NM_002074.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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 11 ACMG points.

• PM1: In a repeat WD 1 (size 30) in uniprot entity GBB1_HUMAN there are 28 pathogenic changes around while only 0 benign (100%) in NM_002074.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-1806513-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1700090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.93
• PP5: Variant 1-1806512-C-A is Pathogenic according to our data. Variant chr1-1806512-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1315582.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNB1	NM_002074.5	c.230G>T	p.Gly77Val	missense_variant	6/12	ENST00000378609.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNB1	ENST00000378609.9	c.230G>T	p.Gly77Val	missense_variant	6/12	1	NM_002074.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 42 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 02, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GNB1 protein function. This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 77 of the GNB1 protein (p.Gly77Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GNB1-related neurodevelopmental delay and hypotonia (PMID: 29174093). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1315582). This variant disrupts the p.Gly77 amino acid residue in GNB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27108799; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.51	D;D;T;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;.;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.3	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.0	.;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.021	D;D;.;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.95
MutPred		0.75		Gain of methylation at K78 (P = 0.0562);Gain of methylation at K78 (P = 0.0562);.;Gain of methylation at K78 (P = 0.0562);Gain of methylation at K78 (P = 0.0562);
MVP		0.94
MPC		3.4
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		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-1737951;