9-98290276-T-G

Variant names:

• chr9-98290276-T-G
• rs10985754
• NM_005458.8:c.*308A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_005458.8(GABBR2):​c.*308A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00514 in 94,938 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (1 hom., cov: 27)
  • Exomes 𝑓: 0.0035 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: GABBR2 NM_005458.8 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00
• 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)
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-98290276-T-G is Benign according to our data. Variant chr9-98290276-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1206699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.*308A>C		3_prime_UTR	Exon 19 of 19	NP_005449.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	ENST00000259455.4	TSL:1 MANE Select	c.*308A>C		3_prime_UTR	Exon 19 of 19	ENSP00000259455.2	O75899
	GABBR2	ENST00000931526.1		c.*308A>C		3_prime_UTR	Exon 18 of 18	ENSP00000601585.1
	GABBR2	ENST00000947376.1		c.*308A>C		downstream_gene	N/A	ENSP00000617435.1

Frequencies

GnomAD3 genomes AF: 0.00515 AC: 489 AN: 94920 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00156

Gnomad AMR AF: 0.00192

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00521

Gnomad SAS AF: 0.00335

Gnomad FIN AF: 0.00293

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.00433

Gnomad OTH AF: 0.00570

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00350 AC: 50 AN: 14286 Hom.: 1 Cov.: 0 AF XY: 0.00363 AC XY: 27 AN XY: 7448

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00128 AC: 1 AN: 784

American (AMR) AF: 0.00483 AC: 2 AN: 414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 694

East Asian (EAS) AF: 0.00293 AC: 4 AN: 1364

South Asian (SAS) AF: 0.00 AC: 0 AN: 132

European-Finnish (FIN) AF: 0.0192 AC: 19 AN: 992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 84

European-Non Finnish (NFE) AF: 0.00248 AC: 22 AN: 8868

Other (OTH) AF: 0.00210 AC: 2 AN: 954

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000134204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00514 AC: 488 AN: 94938 Hom.: 1 Cov.: 27 AF XY: 0.00475 AC XY: 220 AN XY: 46332

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0103 AC: 201 AN: 19456

American (AMR) AF: 0.00201 AC: 21 AN: 10422

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 4 AN: 2770

East Asian (EAS) AF: 0.00523 AC: 18 AN: 3444

South Asian (SAS) AF: 0.00306 AC: 10 AN: 3270

European-Finnish (FIN) AF: 0.00293 AC: 19 AN: 6474

Middle Eastern (MID) AF: 0.0135 AC: 3 AN: 222

European-Non Finnish (NFE) AF: 0.00434 AC: 203 AN: 46826

Other (OTH) AF: 0.00567 AC: 8 AN: 1412

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely 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	-0.81
CADD	Benign	6.2
DANN	Benign	0.73
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

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: rs10985754; hg19: chr9-101052558; COSMIC: COSV105008928; COSMIC: COSV105008928;