rs29267

Positions:

• chr6-29607226-G-A
• chr6-29607226-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001470.4(GABBR1):​c.1993-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,609,372 control chromosomes in the GnomAD database, including 16,485 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1408 hom., cov: 32)
  • Exomes 𝑓: 0.13 (15077 hom.)
• Consequence: GABBR1 NM_001470.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001925
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0830

Genes affected

GABBR1 (HGNC:4070): (gamma-aminobutyric acid type B receptor subunit 1) This gene encodes a receptor for gamma-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the mammalian central nervous system. This receptor functions as a heterodimer with GABA(B) receptor 2. Defects in this gene may underlie brain disorders such as schizophrenia and epilepsy. Alternative splicing generates multiple transcript variants, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABBR1	NM_001470.4	c.1993-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000377034.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABBR1	ENST00000377034.9	c.1993-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001470.4	P1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19008 AN: 152038 Hom.: 1408 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.0618

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.154

GnomAD3 exomes AF: 0.145 AC: 36359 AN: 250680 Hom.: 3270 AF XY: 0.153 AC XY: 20699 AN XY: 135496

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.243

Gnomad SAS exome AF: 0.277

Gnomad FIN exome AF: 0.0565

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.134 AC: 195617 AN: 1457216 Hom.: 15077 Cov.: 31 AF XY: 0.139 AC XY: 100896 AN XY: 725302

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.124

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.0591

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.125 AC: 19017 AN: 152156 Hom.: 1408 Cov.: 32 AF XY: 0.128 AC XY: 9516 AN XY: 74380

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.166

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.0618

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.153

Alfa AF: 0.126 Hom.: 1007

Bravo AF: 0.126

Asia WGS AF: 0.214 AC: 744 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.86
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs29267; hg19: chr6-29575003; COSMIC: COSV63540738; COSMIC: COSV63540738;