rs1554689320

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_005458.8(GABBR2):​c.2077G>T​(p.Gly693Trp) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G693G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

GABBR2
NM_005458.8 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.67
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 4 uncertain in NM_005458.8
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABBR2. . Gene score misZ 4.6253 (greater than the threshold 3.09). Trascript score misZ 4.0975 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 59, neurodevelopmental disorder with poor language and loss of hand skills, atypical Rett syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.939
PP5
Variant 9-98306273-C-A is Pathogenic according to our data. Variant chr9-98306273-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GABBR2NM_005458.8 linkuse as main transcriptc.2077G>T p.Gly693Trp missense_variant 15/19 ENST00000259455.4
GABBR2XM_017015331.3 linkuse as main transcriptc.1783G>T p.Gly595Trp missense_variant 14/18
GABBR2XM_005252316.6 linkuse as main transcriptc.1303G>T p.Gly435Trp missense_variant 13/17
GABBR2XM_017015332.3 linkuse as main transcriptc.1303G>T p.Gly435Trp missense_variant 12/16

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GABBR2ENST00000259455.4 linkuse as main transcriptc.2077G>T p.Gly693Trp missense_variant 15/191 NM_005458.8 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 59 Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 11, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease Company-- -
Epileptic encephalopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 22, 2022This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 496588). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 29100083, 32860008). In at least one individual the variant was observed to be de novo. This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 693 of the GABBR2 protein (p.Gly693Trp). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;.
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Pathogenic
0.62
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Uncertain
2.1
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-7.5
D;.
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;.
Vest4
0.90
MutPred
0.73
Loss of sheet (P = 0.0817);.;
MVP
0.98
MPC
2.2
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.93
gMVP
0.99

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: rs1554689320; hg19: chr9-101068555; API