rs12200969

Variant names:

• chr6-89217247-T-C
• rs12200969
• NM_002042.5:c.76A>G

Variant summary

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

The NM_002042.5(GABRR1):​c.76A>G​(p.Met26Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,613,406 control chromosomes in the GnomAD database, including 102,638 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.36 (10599 hom., cov: 31)
  • Exomes 𝑓: 0.35 (92039 hom.)
• Consequence: GABRR1 NM_002042.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.192

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.671846E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRR1	NM_002042.5	c.76A>G	p.Met26Val	missense_variant	Exon 1 of 10	ENST00000454853.7	NP_002033.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRR1	ENST00000454853.7	c.76A>G	p.Met26Val	missense_variant	Exon 1 of 10	1	NM_002042.5	ENSP00000412673.2

Frequencies

GnomAD3 genomes AF: 0.362 AC: 55014 AN: 151886 Hom.: 10590 Cov.: 31

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.0946

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.360

Gnomad OTH AF: 0.334

GnomAD3 exomes AF: 0.306 AC: 77006 AN: 251254 Hom.: 13150 AF XY: 0.308 AC XY: 41855 AN XY: 135794

Gnomad AFR exome AF: 0.475

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.0999

Gnomad SAS exome AF: 0.278

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.348 AC: 508108 AN: 1461402 Hom.: 92039 Cov.: 36 AF XY: 0.346 AC XY: 251218 AN XY: 727012

Gnomad4 AFR exome AF: 0.471

Gnomad4 AMR exome AF: 0.178

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.0848

Gnomad4 SAS exome AF: 0.279

Gnomad4 FIN exome AF: 0.373

Gnomad4 NFE exome AF: 0.367

Gnomad4 OTH exome AF: 0.339

GnomAD4 genome AF: 0.362 AC: 55052 AN: 152004 Hom.: 10599 Cov.: 31 AF XY: 0.357 AC XY: 26501 AN XY: 74308

Gnomad4 AFR AF: 0.467

Gnomad4 AMR AF: 0.235

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.0944

Gnomad4 SAS AF: 0.268

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.360

Gnomad4 OTH AF: 0.332

Alfa AF: 0.351 Hom.: 17576

Bravo AF: 0.356

TwinsUK AF: 0.355 AC: 1315

ALSPAC AF: 0.367 AC: 1413

ESP6500AA AF: 0.470 AC: 2072

ESP6500EA AF: 0.349 AC: 3000

ExAC AF: 0.316 AC: 38341

Asia WGS AF: 0.262 AC: 913 AN: 3478

EpiCase AF: 0.353

EpiControl AF: 0.338

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	10
DANN	Benign	0.93
DEOGEN2	Benign	0.025	T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	0.00067	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.21	N;N
REVEL	Benign	0.058
Sift	Benign	1.0	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0	B;B
Vest4		0.025
MPC		0.26
ClinPred		0.0034	T
GERP RS		2.9
Varity_R		0.052
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs12200969; hg19: chr6-89926966; COSMIC: COSV65618918;