rs3780422

Variant names:

• chr9-98380522-C-T
• rs3780422
• NM_005458.8:c.1662+5118G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-98380522-C-T
• chr9-98380522-C-A
• chr9-98380522-C-G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

The NM_005458.8(GABBR2):c.1662+5118G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.374 (AC=56,885) in the gnomAD database across 152,160 control chromosomes, including 11,840 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.507. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars).

• Frequency: Genomes: 𝑓 0.37 (11840 hom., cov: 34)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.147
• 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), PanelApp Australia
• complex neurodevelopmental disorder

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5068 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	NM_005458.8	MANE Select	c.1662+5118G>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.1662+5118G>A		intron	N/A	ENSP00000259455.2	O75899
	GABBR2	ENST00000931526.1		c.1596+5118G>A		intron	N/A	ENSP00000601585.1	A0ACI8TL90
	GABBR2	ENST00000947376.1		c.1581+5118G>A		intron	N/A	ENSP00000617435.1	A0ACI8UF98

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.374	AC:56882	Hom:11834	AN:152042	Cov:34
GnomAD4 genome	AF: 0.374	AC:56885	Hom:11840	AN:152160	Cov:34
TOPMed (Bravo)	AF: 0.355	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.400	AC:25609	Hom:5348	AN:64092	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.371	AC:870	Hom:166	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.515	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.457	AC:137	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.387	AC:1346	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.525	AC:3794	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.330	AC:58	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.486	AC:59674	Hom:14556	AN:122804	Cov:
Turkish Variome	AF: 0.408	AC:631	Hom:142	AN:1546	Cov:
UK10K	AF: 0.456	AC:3446	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.525	AC:4701	Hom:1257	AN:8960	Cov:

Showing 14 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	11
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.9
DANN	Benign	0.48
GPN-Star LLR	N/A	-1.2
GPN-Star score	N/A	1.2
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.15

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3780422;

hg19: chr9-101142804;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar