NM_002042.5:c.438C>G

Variant names:

• chr6-89198154-G-C
• rs422751
• NM_002042.5:c.438C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002042.5(GABRR1):​c.438C>G​(p.Asp146Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 29)
• Consequence: GABRR1 NM_002042.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00400
• Publications: 22 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRR1	NM_002042.5	MANE Select	c.438C>G	p.Asp146Glu	missense	Exon 5 of 10	NP_002033.2
	GABRR1	NM_001256703.1		c.387C>G	p.Asp129Glu	missense	Exon 4 of 9	NP_001243632.1
	GABRR1	NM_001256704.1		c.177C>G	p.Asp59Glu	missense	Exon 6 of 11	NP_001243633.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRR1	ENST00000454853.7	TSL:1 MANE Select	c.438C>G	p.Asp146Glu	missense	Exon 5 of 10	ENSP00000412673.2
	GABRR1	ENST00000435811.5	TSL:2	c.387C>G	p.Asp129Glu	missense	Exon 4 of 9	ENSP00000394687.1
	GABRR1	ENST00000369451.7	TSL:5	c.177C>G	p.Asp59Glu	missense	Exon 7 of 12	ENSP00000358463.3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 57

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.76	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.0040
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.82
MutPred		0.58		Loss of MoRF binding (P = 0.1185)
MVP		0.82
MPC		0.74
ClinPred		0.99	D
GERP RS		-2.4
Varity_R		0.59
gMVP		0.41
Mutation Taster		=35/65	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: rs422751; hg19: chr6-89907873;