9-98306266-C-T

Variant names:

• chr9-98306266-C-T
• rs1554689319
• NM_005458.8:c.2084G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005458.8(GABBR2):​c.2084G>A​(p.Ser695Asn) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S695I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABBR2 NM_005458.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.73
• Publications: 0 publications found

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]

GABBR2 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 59

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with poor language and loss of hand skills

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 6 uncertain in NM_005458.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-98306266-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 496589.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 9-98306266-C-T is Pathogenic according to our data. Variant chr9-98306266-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1691275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.2084G>A	p.Ser695Asn	missense_variant	Exon 15 of 19	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.1790G>A	p.Ser597Asn	missense_variant	Exon 14 of 18		XP_016870820.1
GABBR2	XM_005252316.6	c.1310G>A	p.Ser437Asn	missense_variant	Exon 13 of 17		XP_005252373.1
GABBR2	XM_017015332.3	c.1310G>A	p.Ser437Asn	missense_variant	Exon 12 of 16		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.2084G>A	p.Ser695Asn	missense_variant	Exon 15 of 19	1	NM_005458.8	ENSP00000259455.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Dec 10, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in a patient with infantile epileptic spasm syndrome in the published literature (PMID: 37583270); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37583270) -

Neurodevelopmental disorder with poor language and loss of hand skills;C4693550:Developmental and epileptic encephalopathy, 59 Pathogenic:1

Jan 31, 2022

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2084G>A variant is not present in publicly available population databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD), dbSNP and Indian Exome Database. The variant is also not present in our in-house exome database. The variant was not reported earlier to ClinVar, Human Genome Mutation Database (HGMD) and OMIM databases in any affected individuals.In-silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD, Varsome etc. predicted this variant to be likely deleterious, however these predictions were not confirmed by any published functional studies. An alternative variant c.2084G>T has been classified as pathogenic by UniProt Variants as per ACMG guidelines previously and reported to databases like Clinvar and HGMD (PMID: 29100083, 28856709, 25262651). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.9	L;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.7	D;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0080	D;.
Polyphen		0.99	D;.
Vest4		0.72
MutPred		0.89		Loss of sheet (P = 0.0817);.;
MVP		0.92
MPC		1.7
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.99
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs1554689319; hg19: chr9-101068548;