9-98496599-T-C

Variant names:

• chr9-98496599-T-C
• rs1000440
• NM_005458.8:c.631-85A>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.631-85A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 881,838 control chromosomes in the GnomAD database, including 156,184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28735 hom., cov: 31)
  • Exomes 𝑓: 0.58 (127449 hom.)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.58
• Publications: 7 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=-0.96).
• BP6: Variant 9-98496599-T-C is Benign according to our data. Variant chr9-98496599-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.631-85A>G		intron_variant	Intron 3 of 18	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.337-85A>G		intron_variant	Intron 2 of 17		XP_016870820.1
GABBR2	XM_005252316.6	c.-144-85A>G		intron_variant	Intron 1 of 16		XP_005252373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.631-85A>G		intron_variant	Intron 3 of 18	1	NM_005458.8	ENSP00000259455.2

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91923 AN: 151838 Hom.: 28708 Cov.: 31

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.666

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.576

GnomAD4 exome AF: 0.579 AC: 422950 AN: 729880 Hom.: 127449 AF XY: 0.575 AC XY: 223155 AN XY: 388312

African (AFR) AF: 0.685 AC: 13579 AN: 19818

American (AMR) AF: 0.429 AC: 17517 AN: 40846

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 13812 AN: 20868

East Asian (EAS) AF: 0.196 AC: 7096 AN: 36130

South Asian (SAS) AF: 0.443 AC: 30755 AN: 69452

European-Finnish (FIN) AF: 0.604 AC: 28875 AN: 47820

Middle Eastern (MID) AF: 0.597 AC: 2297 AN: 3850

European-Non Finnish (NFE) AF: 0.633 AC: 287796 AN: 454926

Other (OTH) AF: 0.587 AC: 21223 AN: 36170

GnomAD4 genome AF: 0.605 AC: 91996 AN: 151958 Hom.: 28735 Cov.: 31 AF XY: 0.597 AC XY: 44319 AN XY: 74246

African (AFR) AF: 0.679 AC: 28126 AN: 41430

American (AMR) AF: 0.511 AC: 7812 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 2310 AN: 3470

East Asian (EAS) AF: 0.190 AC: 978 AN: 5146

South Asian (SAS) AF: 0.419 AC: 2012 AN: 4802

European-Finnish (FIN) AF: 0.603 AC: 6350 AN: 10534

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.623 AC: 42338 AN: 67970

Other (OTH) AF: 0.572 AC: 1209 AN: 2114

Alfa AF: 0.602 Hom.: 72062

Bravo AF: 0.600

Asia WGS AF: 0.335 AC: 1165 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.016
DANN	Benign	0.18
PhyloP100		-2.6
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: rs1000440; hg19: chr9-101258881;