rs29267

Variant names:

• chr6-29607226-G-A
• rs29267
• NM_001470.4:c.1993-8C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001470.4(GABBR1):​c.1993-8C>T variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00001925
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0830
• Publications: 16 publications found

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]

GABBR1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with language delay and variable cognitive abnormalities

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001470.4. 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
	GABBR1	NM_001470.4	MANE Select	c.1993-8C>T		splice_region intron	N/A	NP_001461.1	A0A1U9X7R0
	GABBR1	NM_021904.4		c.1807-8C>T		splice_region intron	N/A	NP_068704.2	Q9UBS5-3
	GABBR1	NM_021903.3		c.1642-8C>T		splice_region intron	N/A	NP_068703.1	Q5SUJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR1	ENST00000377034.9	TSL:1 MANE Select	c.1993-8C>T		splice_region intron	N/A	ENSP00000366233.4	Q9UBS5-1
	GABBR1	ENST00000377012.9	TSL:1	c.1642-8C>T		splice_region intron	N/A	ENSP00000366211.4	Q9UBS5-2
	GABBR1	ENST00000476670.3	TSL:4	c.2008-8C>T		splice_region intron	N/A	ENSP00000417332.2	C9J342

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

GnomAD2 exomes AF: 0.145 AC: 36359 AN: 250680 AF XY: 0.153

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 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

African (AFR) AF: 0.107 AC: 3589 AN: 33388

American (AMR) AF: 0.124 AC: 5552 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 4481 AN: 26118

East Asian (EAS) AF: 0.224 AC: 8877 AN: 39682

South Asian (SAS) AF: 0.281 AC: 24255 AN: 86184

European-Finnish (FIN) AF: 0.0591 AC: 3150 AN: 53292

Middle Eastern (MID) AF: 0.236 AC: 1345 AN: 5706

European-Non Finnish (NFE) AF: 0.122 AC: 135256 AN: 1107864

Other (OTH) AF: 0.151 AC: 9112 AN: 60260

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

African (AFR) AF: 0.107 AC: 4459 AN: 41510

American (AMR) AF: 0.120 AC: 1828 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 574 AN: 3468

East Asian (EAS) AF: 0.253 AC: 1302 AN: 5154

South Asian (SAS) AF: 0.296 AC: 1425 AN: 4814

European-Finnish (FIN) AF: 0.0618 AC: 655 AN: 10598

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8283 AN: 68004

Other (OTH) AF: 0.153 AC: 324 AN: 2112

Alfa AF: 0.126 Hom.: 1371

Bravo AF: 0.126

Asia WGS AF: 0.214 AC: 744 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.86
DANN	Benign	0.65
PhyloP100		-0.083
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

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

Other links and lift over

dbSNP: rs29267;

hg19: chr6-29575003;

COSMIC: COSV63540738;

COSMIC: COSV63540738;