Genetic Variant GABRR1:c.123-5G>A (chr6-89203490-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PVS1_ModerateBA1

The NM_001256704.1(GABRR1):c.-142-2G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 1,600,630 control chromosomes in the GnomAD database, including 364,486 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.69 ( 35922 hom., cov: 32)

Exomes 𝑓: 0.67 ( 328564 hom. )

Consequence

GABRR1
NM_001256704.1 splice_acceptor, intron

Scores

Splicing: ADA: 0.1825

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.25

Variant links:

Genes affected

GABRR1 (HGNC:4090): (gamma-aminobutyric acid type A receptor subunit rho1) GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA receptors, which are ligand-gated chloride channels. GABRR1 is a member of the rho subunit family. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

GABRR1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.045801528 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.4, offset of 0 (no position change), new splice context is: tttatttttaatgttcatAGtag. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRR1	NM_002042.5 link	c.123-5G>A		splice_region_variant, intron_variant	Intron 1 of 9	ENST00000454853.7	NP_002033.2	P24046-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GABRR1	ENST00000454853.7 link	c.123-5G>A	splice_region_variant, intron_variant	Intron 1 of 9	1	NM_002042.5	ENSP00000412673.2	P24046-1
GABRR1	ENST00000435811.5 link	c.123-2225G>A	intron_variant	Intron 1 of 8	2		ENSP00000394687.1	P24046-2
GABRR1	ENST00000369451.7 link	c.-139-5G>A	splice_region_variant, intron_variant	Intron 3 of 11	5		ENSP00000358463.3	P24046-3
GABRR1	ENST00000457434.1 link	n.*84-5G>A	splice_region_variant, intron_variant	Intron 2 of 10	5		ENSP00000410130.1	F8WB88

Frequencies

GnomAD3 genomes

AF:

0.685

AC:

103950

AN:

151694

Hom.:

35885

Cov.:

show subpopulations

Gnomad AFR

AF:

0.679

Gnomad AMI

AF:

0.761

Gnomad AMR

AF:

0.739

Gnomad ASJ

AF:

0.643

Gnomad EAS

AF:

0.919

Gnomad SAS

AF:

0.705

Gnomad FIN

AF:

0.704

Gnomad MID

AF:

0.646

Gnomad NFE

AF:

0.657

Gnomad OTH

AF:

0.673

GnomAD3 exomes

AF:

0.703

AC:

176574

AN:

251096

Hom.:

62852

AF XY:

0.698

AC XY:

94697

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.672

Gnomad AMR exome

AF:

0.805

Gnomad ASJ exome

AF:

0.648

Gnomad EAS exome

AF:

0.916

Gnomad SAS exome

AF:

0.695

Gnomad FIN exome

AF:

0.700

Gnomad NFE exome

AF:

0.651

Gnomad OTH exome

AF:

0.693

GnomAD4 exome

AF:

0.670

AC:

971383

AN:

1448818

Hom.:

328564

Cov.:

AF XY:

0.670

AC XY:

483764

AN XY:

721538

show subpopulations

Gnomad4 AFR exome

AF:

0.676

Gnomad4 AMR exome

AF:

0.798

Gnomad4 ASJ exome

AF:

0.649

Gnomad4 EAS exome

AF:

0.906

Gnomad4 SAS exome

AF:

0.694

Gnomad4 FIN exome

AF:

0.696

Gnomad4 NFE exome

AF:

0.654

Gnomad4 OTH exome

AF:

0.685

GnomAD4 genome

AF:

0.685

AC:

104033

AN:

151812

Hom.:

35922

Cov.:

AF XY:

0.689

AC XY:

51123

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.679

Gnomad4 AMR

AF:

0.740

Gnomad4 ASJ

AF:

0.643

Gnomad4 EAS

AF:

0.918

Gnomad4 SAS

AF:

0.705

Gnomad4 FIN

AF:

0.704

Gnomad4 NFE

AF:

0.657

Gnomad4 OTH

AF:

0.675

Alfa

AF:

0.658

Hom.:

34851

Bravo

AF:

0.688

Asia WGS

AF:

0.827

AC:

2875

AN:

3478

EpiCase

AF:

0.661

EpiControl

AF:

0.653

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.18

dbscSNV1_RF

Pathogenic

0.77

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.71

Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over