6-89185409-C-T

Variant names:

• chr6-89185409-C-T
• rs1771872590
• NM_002042.5:c.697G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002042.5(GABRR1):​c.697G>A​(p.Gly233Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G233C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GABRR1 NM_002042.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

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.697G>A	p.Gly233Ser	missense	Exon 7 of 10	NP_002033.2	P24046-1
	GABRR1	NM_001256703.1		c.646G>A	p.Gly216Ser	missense	Exon 6 of 9	NP_001243632.1	P24046-2
	GABRR1	NM_001256704.1		c.436G>A	p.Gly146Ser	missense	Exon 8 of 11	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.697G>A	p.Gly233Ser	missense	Exon 7 of 10	ENSP00000412673.2	P24046-1
	GABRR1	ENST00000435811.5	TSL:2	c.646G>A	p.Gly216Ser	missense	Exon 6 of 9	ENSP00000394687.1	P24046-2
	GABRR1	ENST00000369451.7	TSL:5	c.436G>A	p.Gly146Ser	missense	Exon 9 of 12	ENSP00000358463.3	P24046-3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461480 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727072

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111668

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74268

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.065	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.71
MutPred		0.42		Gain of ubiquitination at K231 (P = 0.0605)
MVP		0.96
MPC		0.92
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.81
gMVP		0.57
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs1771872590; hg19: chr6-89895128;