rs869312824
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_002074.5(GNB1):c.284T>C(p.Leu95Pro) 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 (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
GNB1
NM_002074.5 missense
NM_002074.5 missense
Scores
13
3
3
Clinical Significance
Conservation
PhyloP100: 9.11
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_002074.5
PM2
Very rare variant in population databases, with high coverage;
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, 0.857
PP5
Variant 1-1804565-A-G is Pathogenic according to our data. Variant chr1-1804565-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1804565-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GNB1 | NM_002074.5 | c.284T>C | p.Leu95Pro | missense_variant | 7/12 | ENST00000378609.9 | NP_002065.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNB1 | ENST00000378609.9 | c.284T>C | p.Leu95Pro | missense_variant | 7/12 | 1 | NM_002074.5 | ENSP00000367872.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Department of Pediatrics, Samsung Medical Center, Samsung Medical Center | - | - - |
Hypotonia;C0036572:Seizure;na:Neurodevelopmental Disability Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | May 05, 2016 | - - |
Hypotonia;C0028738:Nystagmus;C0036572:Seizure;C0038379:Strabismus;C0232466:Feeding difficulties;C0454641:Expressive language delay;C0456070:Growth delay;C0557874:Global developmental delay;C0560046:Inability to walk;C1838391:Limb hypertonia;C2315100:Failure to thrive;C3714756:Intellectual disability;C4021219:Multifocal epileptiform discharges;C4048268:Cerebral visual impairment Pathogenic:1
Pathogenic, no assertion criteria provided | research | Genomics And Bioinformatics Analysis Resource, Columbia University | Feb 10, 2016 | - - |
Hypotonia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Jul 11, 2022 | de novo, previously published. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 12, 2021 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces leucine with proline at codon 95 of the GNB1 protein (p.Leu95Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with GNB1-related conditions (PMID: 27108799, 30194818). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 224716). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). - |
Intellectual disability, autosomal dominant 42 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;.;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;D;D;D;D
REVEL
Uncertain
Sift
Pathogenic
.;D;D;D;D
Sift4G
Uncertain
D;D;.;.;.
Polyphen
D;D;.;.;.
Vest4
MutPred
Gain of catalytic residue at P94 (P = 0.0107);Gain of catalytic residue at P94 (P = 0.0107);.;Gain of catalytic residue at P94 (P = 0.0107);Gain of catalytic residue at P94 (P = 0.0107);
MVP
MPC
4.3
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at