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

Scores

13
3
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 9.11
Variant links:
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
GNB1NM_002074.5 linkuse as main transcriptc.284T>C p.Leu95Pro missense_variant 7/12 ENST00000378609.9 NP_002065.1 P62873-1A0A140VJJ8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GNB1ENST00000378609.9 linkuse as main transcriptc.284T>C p.Leu95Pro missense_variant 7/121 NM_002074.5 ENSP00000367872.3 P62873-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
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 submitterresearchDepartment of Pediatrics, Samsung Medical Center, Samsung Medical Center-- -
Hypotonia;C0036572:Seizure;na:Neurodevelopmental Disability Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of WashingtonMay 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 providedresearchGenomics And Bioinformatics Analysis Resource, Columbia UniversityFeb 10, 2016- -
Hypotonia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGénétique des Maladies du Développement, Hospices Civils de LyonJul 11, 2022de novo, previously published. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 12, 2021For 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 providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
33
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.82
D;D;T;.;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;.;D;D;D
M_CAP
Benign
0.034
D
MetaRNN
Pathogenic
0.86
D;D;D;D;D
MetaSVM
Benign
-1.2
T
MutationAssessor
Pathogenic
3.1
M;M;.;.;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-6.3
.;D;D;D;D
REVEL
Uncertain
0.56
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Uncertain
0.0050
D;D;.;.;.
Polyphen
1.0
D;D;.;.;.
Vest4
0.95
MutPred
0.68
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
0.87
MPC
4.3
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.98
gMVP
0.94

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs869312824; hg19: chr1-1736004; API