NM_002042.5:c.123-5G>A

Variant names:

• chr6-89203490-C-T
• rs4590242
• NM_002042.5:c.123-5G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3 BA1

The NM_002042.5(GABRR1):​c.123-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 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_002042.5 splice_region, intron
• Scores: Splicing: ADA: 0.1825
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• Publications: 13 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002042.5. 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
	GABRR1	NM_002042.5	MANE Select	c.123-5G>A		splice_region intron	N/A	NP_002033.2	P24046-1
	GABRR1	NM_001256703.1		c.123-2225G>A		intron	N/A	NP_001243632.1	P24046-2
	GABRR1	NM_001256704.1		c.-142-2G>A		splice_acceptor intron	N/A	NP_001243633.1	P24046-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRR1	ENST00000454853.7	TSL:1 MANE Select	c.123-5G>A		splice_region intron	N/A	ENSP00000412673.2	P24046-1
	GABRR1	ENST00000435811.5	TSL:2	c.123-2225G>A		intron	N/A	ENSP00000394687.1	P24046-2
	GABRR1	ENST00000369451.7	TSL:5	c.-139-5G>A		splice_region intron	N/A	ENSP00000358463.3	P24046-3

Frequencies

GnomAD3 genomes AF: 0.685 AC: 103950 AN: 151694 Hom.: 35885 Cov.: 32

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

GnomAD2 exomes AF: 0.703 AC: 176574 AN: 251096 AF XY: 0.698

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 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.: 33 AF XY: 0.670 AC XY: 483764 AN XY: 721538

African (AFR) AF: 0.676 AC: 22452 AN: 33230

American (AMR) AF: 0.798 AC: 35677 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 16909 AN: 26066

East Asian (EAS) AF: 0.906 AC: 35903 AN: 39614

South Asian (SAS) AF: 0.694 AC: 59660 AN: 85990

European-Finnish (FIN) AF: 0.696 AC: 37167 AN: 53406

Middle Eastern (MID) AF: 0.595 AC: 3418 AN: 5742

European-Non Finnish (NFE) AF: 0.654 AC: 719103 AN: 1100094

Other (OTH) AF: 0.685 AC: 41094 AN: 59966

GnomAD4 genome AF: 0.685 AC: 104033 AN: 151812 Hom.: 35922 Cov.: 32 AF XY: 0.689 AC XY: 51123 AN XY: 74194

African (AFR) AF: 0.679 AC: 28064 AN: 41352

American (AMR) AF: 0.740 AC: 11276 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 2229 AN: 3464

East Asian (EAS) AF: 0.918 AC: 4743 AN: 5164

South Asian (SAS) AF: 0.705 AC: 3391 AN: 4812

European-Finnish (FIN) AF: 0.704 AC: 7439 AN: 10560

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.657 AC: 44587 AN: 67906

Other (OTH) AF: 0.675 AC: 1422 AN: 2108

Alfa AF: 0.665 Hom.: 90770

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	17
DANN	Benign	0.58
PhyloP100		1.2
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4590242; hg19: chr6-89913209; COSMIC: COSV65620511; COSMIC: COSV65620511;