rs922847767
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM5PP2PP3_ModeratePP5_Very_Strong
The NM_005458.8(GABBR2):c.1699G>A(p.Ala567Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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. A567V) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
GABBR2
NM_005458.8 missense
NM_005458.8 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 7.51
Genes affected
GABBR2 (HGNC:4507): (gamma-aminobutyric acid type B receptor subunit 2) The multi-pass membrane protein encoded by this gene belongs to the G-protein coupled receptor 3 family and GABA-B receptor subfamily. The GABA-B receptors inhibit neuronal activity through G protein-coupled second-messenger systems, which regulate the release of neurotransmitters, and the activity of ion channels and adenylyl cyclase. This receptor subunit forms an active heterodimeric complex with GABA-B receptor subunit 1, neither of which is effective on its own. Allelic variants of this gene have been associated with nicotine dependence.[provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr9-98371534-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1073462.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
Missense variant where missense usually causes diseases, GABBR2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.87
PP5
?
Variant 9-98371535-C-T is Pathogenic according to our data. Variant chr9-98371535-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 446211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-98371535-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABBR2 | NM_005458.8 | c.1699G>A | p.Ala567Thr | missense_variant | 12/19 | ENST00000259455.4 | |
GABBR2 | XM_017015331.3 | c.1405G>A | p.Ala469Thr | missense_variant | 11/18 | ||
GABBR2 | XM_005252316.6 | c.925G>A | p.Ala309Thr | missense_variant | 10/17 | ||
GABBR2 | XM_017015332.3 | c.925G>A | p.Ala309Thr | missense_variant | 9/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABBR2 | ENST00000259455.4 | c.1699G>A | p.Ala567Thr | missense_variant | 12/19 | 1 | NM_005458.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1459618Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 726324
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1459618
Hom.:
Cov.:
28
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0
AN XY:
726324
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neurodevelopmental disorder with poor language and loss of hand skills Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 30, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Same nucleotide change resulting in same amino acid change has been previously reported multiple times as de novo in similarly affected indivisual (PMID: 25533962, 28688840 PS2, PS4_M). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Nov 03, 2020 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jul 28, 2020 | PS2, PS4, PP3, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Rett syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | case-control;in vitro;in vivo;research | Choi Lab, Seoul National University | Sep 22, 2017 | We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model. GABBR2 is a genetic factor that determines RTT- or EE-like phenotype expression depending on the variant positions. GABBR2-mediated γ-aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 03, 2016 | - - |
GABBR2-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 30, 2023 | The GABBR2 c.1699G>A variant is predicted to result in the amino acid substitution p.Ala567Thr. This variant has been reported as a recurrent de novo variant in individuals with Rett-syndrome like phenotypes and non-specified neurodevelopmental disorders (Lopes et al. 2016. PubMed ID: 26740508; Lucariello et al. 2016. PubMed ID: 27541642; Kosmicki et al. 2017. PubMed ID: 28191890; Takata A et al. 2018. PubMed ID: 29346770; McRae et al. 2017. PubMed ID: 28135719; Yoo et al. 2017. PubMed ID: 28856709 ). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Epileptic encephalopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 567 of the GABBR2 protein (p.Ala567Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GABBR2-related conditions (PMID: 26740508, 27541642, 28856709). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 446211). 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 not expected to disrupt GABBR2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GABBR2 function (PMID: 28856709). For these reasons, this variant has been classified as Pathogenic. - |
GABBR2-related disorders Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a de novo heterozygous change in multiple unrelated patients with autism spectrum disorder, motor and language developmental delay, developmental regression, stereotypies, sleep disturbance, and muscular hypotonia with or without epileptic encephalopathy (PMID: 26740508, 27541642, 28191890, 28856709, 28867141, 29346770). A different amino acid change at the same residue (p.Ala567Val) has been observed in individuals with similar clinical phenotype and in at least one of these individuals, this variant was detected to be de novo (Variation ID: 1073462, Invitae internal data). The GABBR2 gene is constrained against variation (Z-score= 4.63 and pLI = 1) and missense variants are a common mechanism of disease (HGMD, ClinVar database). Experimental studies showed that presence of the p.Ala567Thr variant resulted in abnormal protein activity in HEK293 cells without altering protein expression and subcellular localization; furthermore, this variant caused abnormal behaviors in tadpoles (PMID: 28856709). The c.1699G>A (p.Ala567Thr) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1699G>A (p.Ala567Thr) variant is classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Uncertain
D;.
Polyphen
D;.
Vest4
MutPred
Gain of MoRF binding (P = 0.1367);.;
MVP
MPC
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