9-98453895-T-C

Variant names:

• chr9-98453895-T-C
• rs3802477
• NM_005458.8:c.1236+86A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005458.8(GABBR2):​c.1236+86A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 892,898 control chromosomes in the GnomAD database, including 1,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (194 hom., cov: 32)
  • Exomes 𝑓: 0.056 (1451 hom.)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.53
• Publications: 3 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)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-98453895-T-C is Benign according to our data. Variant chr9-98453895-T-C is described in ClinVar as Benign. ClinVar VariationId is 1264838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005458.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	NM_005458.8	MANE Select	c.1236+86A>G		intron	N/A	NP_005449.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	ENST00000259455.4	TSL:1 MANE Select	c.1236+86A>G		intron	N/A	ENSP00000259455.2	O75899
	GABBR2	ENST00000931526.1		c.1170+86A>G		intron	N/A	ENSP00000601585.1
	GABBR2	ENST00000947376.1		c.1236+86A>G		intron	N/A	ENSP00000617435.1

Frequencies

GnomAD3 genomes AF: 0.0422 AC: 6413 AN: 152136 Hom.: 195 Cov.: 32

Gnomad AFR AF: 0.00997

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0499

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0529

Gnomad FIN AF: 0.0586

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0503

Gnomad OTH AF: 0.0406

GnomAD4 exome AF: 0.0558 AC: 41336 AN: 740644 Hom.: 1451 AF XY: 0.0548 AC XY: 21423 AN XY: 390628

African (AFR) AF: 0.0102 AC: 200 AN: 19596

American (AMR) AF: 0.0738 AC: 2995 AN: 40596

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 448 AN: 18960

East Asian (EAS) AF: 0.153 AC: 5561 AN: 36418

South Asian (SAS) AF: 0.0475 AC: 3065 AN: 64502

European-Finnish (FIN) AF: 0.0598 AC: 3075 AN: 51420

Middle Eastern (MID) AF: 0.0111 AC: 40 AN: 3600

European-Non Finnish (NFE) AF: 0.0514 AC: 24131 AN: 469472

Other (OTH) AF: 0.0505 AC: 1821 AN: 36080

GnomAD4 genome AF: 0.0421 AC: 6414 AN: 152254 Hom.: 194 Cov.: 32 AF XY: 0.0435 AC XY: 3235 AN XY: 74436

African (AFR) AF: 0.00992 AC: 412 AN: 41552

American (AMR) AF: 0.0498 AC: 762 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3464

East Asian (EAS) AF: 0.147 AC: 761 AN: 5178

South Asian (SAS) AF: 0.0533 AC: 257 AN: 4818

European-Finnish (FIN) AF: 0.0586 AC: 622 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0503 AC: 3420 AN: 68018

Other (OTH) AF: 0.0406 AC: 86 AN: 2116

Alfa AF: 0.0498 Hom.: 177

Bravo AF: 0.0415

Asia WGS AF: 0.0900 AC: 313 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.14
DANN	Benign	0.51
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs3802477; hg19: chr9-101216177; COSMIC: COSV52303061; COSMIC: COSV52303061;