rs1554689313

Positions:

• chr9-98306231-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The ENST00000259455.4(GABBR2):​c.2119G>A​(p.Ala707Thr) 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. A707A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABBR2 ENST00000259455.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.73

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in ENST00000259455.4
• 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, 0.851
• PP5: Variant 9-98306231-C-T is Pathogenic according to our data. Variant chr9-98306231-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496592.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-98306231-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.2119G>A	p.Ala707Thr	missense_variant	15/19	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.1825G>A	p.Ala609Thr	missense_variant	14/18		XP_016870820.1
GABBR2	XM_005252316.6	c.1345G>A	p.Ala449Thr	missense_variant	13/17		XP_005252373.1
GABBR2	XM_017015332.3	c.1345G>A	p.Ala449Thr	missense_variant	12/16		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.2119G>A	p.Ala707Thr	missense_variant	15/19	1	NM_005458.8	ENSP00000259455	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with poor language and loss of hand skills Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 15, 2018

- -

Developmental and epileptic encephalopathy, 59 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Oct 01, 2021

PM2, PM6, PP3, PP4, PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.9	D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.12	T;.
Polyphen		1.0	D;.
Vest4		0.68
MutPred		0.57		Loss of helix (P = 0.2662);.;
MVP		0.90
MPC		1.5
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.79
gMVP		0.92

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: rs1554689313; hg19: chr9-101068513;