rs869312824

Variant names:

• chr1-1804565-A-G
• rs869312824
• NM_002074.5:c.284T>C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• 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]

ACMG classification

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 the GNB1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 33 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 3.8328 (above the threshold of 3.09). Trascript score misZ: 3.4817 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
GNB1	NM_002074.5	c.284T>C	p.Leu95Pro	missense_variant	Exon 7 of 12	ENST00000378609.9	NP_002065.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNB1	ENST00000378609.9	c.284T>C	p.Leu95Pro	missense_variant	Exon 7 of 12	1	NM_002074.5	ENSP00000367872.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly Pathogenic:1

-

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hypotonia;C0036572:Seizure;na:Neurodevelopmental Disability Pathogenic:1

May 05, 2016

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

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

Feb 10, 2016

Genomics And Bioinformatics Analysis Resource, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Pathogenic:1

Aug 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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"). ClinVar contains an entry for this variant (Variation ID: 224716). 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. This variant is not present in population databases (ExAC no frequency). 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. -

Hypotonia Pathogenic:1

Jul 11, 2022

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

de novo, previously published. -

Intellectual disability, autosomal dominant 42 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

Other links and lift over

dbSNP: rs869312824; hg19: chr1-1736004;