9-98306256-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005458.8(GABBR2):​c.2094C>A​(p.Asn698Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

GABBR2
NM_005458.8 missense

Scores

7
8
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.126
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GABBR2NM_005458.8 linkc.2094C>A p.Asn698Lys missense_variant Exon 15 of 19 ENST00000259455.4 NP_005449.5 O75899H9NIL8
GABBR2XM_017015331.3 linkc.1800C>A p.Asn600Lys missense_variant Exon 14 of 18 XP_016870820.1
GABBR2XM_005252316.6 linkc.1320C>A p.Asn440Lys missense_variant Exon 13 of 17 XP_005252373.1
GABBR2XM_017015332.3 linkc.1320C>A p.Asn440Lys missense_variant Exon 12 of 16 XP_016870821.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GABBR2ENST00000259455.4 linkc.2094C>A p.Asn698Lys missense_variant Exon 15 of 19 1 NM_005458.8 ENSP00000259455.2 O75899

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Uncertain
0.064
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;.
Eigen
Benign
0.13
Eigen_PC
Benign
-0.052
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Pathogenic
0.51
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Uncertain
2.4
M;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-5.6
D;.
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0020
D;.
Sift4G
Uncertain
0.016
D;.
Polyphen
1.0
D;.
Vest4
0.92
MutPred
0.89
Gain of methylation at N698 (P = 0.0197);.;
MVP
0.88
MPC
1.6
ClinPred
1.0
D
GERP RS
-1.3
Varity_R
0.96
gMVP
1.0

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: rs763391651; hg19: chr9-101068538; API