9-98542066-C-T

Variant names:

• chr9-98542066-C-T
• rs2184026
• NM_005458.8:c.460-23G>A

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.460-23G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,604,824 control chromosomes in the GnomAD database, including 43,661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3676 hom., cov: 33)
  • Exomes 𝑓: 0.22 (39985 hom.)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.87
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-98542066-C-T is Benign according to our data. Variant chr9-98542066-C-T is described in ClinVar as Benign. ClinVar VariationId is 1277285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.481 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.460-23G>A		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.460-23G>A		intron	N/A	ENSP00000259455.2
	GABBR2	ENST00000931526.1		c.460-23G>A		intron	N/A	ENSP00000601585.1
	GABBR2	ENST00000947376.1		c.460-23G>A		intron	N/A	ENSP00000617435.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29776 AN: 152056 Hom.: 3666 Cov.: 33

Gnomad AFR AF: 0.0665

Gnomad AMI AF: 0.310

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.215

GnomAD2 exomes AF: 0.248 AC: 61014 AN: 246172 AF XY: 0.246

Gnomad AFR exome AF: 0.0623

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.498

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.242

GnomAD4 exome AF: 0.224 AC: 326005 AN: 1452650 Hom.: 39985 Cov.: 29 AF XY: 0.225 AC XY: 162322 AN XY: 722848

African (AFR) AF: 0.0543 AC: 1807 AN: 33294

American (AMR) AF: 0.311 AC: 13848 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 5728 AN: 26026

East Asian (EAS) AF: 0.546 AC: 21587 AN: 39502

South Asian (SAS) AF: 0.224 AC: 19155 AN: 85590

European-Finnish (FIN) AF: 0.257 AC: 13649 AN: 53140

Middle Eastern (MID) AF: 0.186 AC: 1072 AN: 5760

European-Non Finnish (NFE) AF: 0.213 AC: 235705 AN: 1104810

Other (OTH) AF: 0.224 AC: 13454 AN: 60012

GnomAD4 genome AF: 0.196 AC: 29795 AN: 152174 Hom.: 3676 Cov.: 33 AF XY: 0.205 AC XY: 15222 AN XY: 74390

African (AFR) AF: 0.0663 AC: 2753 AN: 41534

American (AMR) AF: 0.275 AC: 4202 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 767 AN: 3472

East Asian (EAS) AF: 0.497 AC: 2566 AN: 5168

South Asian (SAS) AF: 0.231 AC: 1116 AN: 4828

European-Finnish (FIN) AF: 0.280 AC: 2957 AN: 10566

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14623 AN: 68004

Other (OTH) AF: 0.218 AC: 460 AN: 2112

Alfa AF: 0.213 Hom.: 4441

Bravo AF: 0.193

Asia WGS AF: 0.331 AC: 1152 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.84
CADD	Benign	1.8
DANN	Benign	0.64
PhyloP100		-1.9
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: rs2184026; hg19: chr9-101304348; COSMIC: COSV52304571;