rs1554698962
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_005458.8(GABBR2):c.1450A>G(p.Ile484Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
GABBR2
NM_005458.8 missense
NM_005458.8 missense
Scores
1
1
17
Clinical Significance
Conservation
PhyloP100: 5.99
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, GABBR2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.21611032).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GABBR2 | NM_005458.8 | c.1450A>G | p.Ile484Val | missense_variant | 10/19 | ENST00000259455.4 | |
GABBR2 | XM_017015331.3 | c.1156A>G | p.Ile386Val | missense_variant | 9/18 | ||
GABBR2 | XM_005252316.6 | c.676A>G | p.Ile226Val | missense_variant | 8/17 | ||
GABBR2 | XM_017015332.3 | c.676A>G | p.Ile226Val | missense_variant | 7/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GABBR2 | ENST00000259455.4 | c.1450A>G | p.Ile484Val | missense_variant | 10/19 | 1 | NM_005458.8 | P1 | |
GABBR2 | ENST00000637410.1 | n.1228A>G | non_coding_transcript_exon_variant | 10/19 | 5 | ||||
GABBR2 | ENST00000634314.1 | upstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461332Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727016
GnomAD4 exome
AF:
AC:
2
AN:
1461332
Hom.:
Cov.:
30
AF XY:
AC XY:
1
AN XY:
727016
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Epileptic encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 03, 2017 | In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GABBR2-related disease. This sequence change replaces isoleucine with valine at codon 484 of the GABBR2 protein (p.Ile484Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of sheet (P = 0.0344);
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