Genetic Variant GRK1:p.Gly144Trp (chr13-113667816-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002929.3(GRK1):c.430G>T(p.Gly144Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000276 in 1,448,510 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G144A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

GRK1
NM_002929.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.34

Publications

0 publications found

Variant links:

Genes affected

GRK1 (HGNC:10013): (G protein-coupled receptor kinase 1) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates rhodopsin and initiates its deactivation. Defects in GRK1 are known to cause Oguchi disease 2 (also known as stationary night blindness Oguchi type-2). [provided by RefSeq, Jul 2008]

GRK1 Gene-Disease associations (from GenCC):

Oguchi disease
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Oguchi disease-2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

GRK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002929.3. 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
	GRK1	NM_002929.3	MANE Select	c.430G>T	p.Gly144Trp	missense	Exon 1 of 7	NP_002920.1	Q15835

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK1	ENST00000335678.7	TSL:1 MANE Select	c.430G>T	p.Gly144Trp	missense	Exon 1 of 7	ENSP00000334876.5	Q15835

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000130

AC:

AN:

231410

AF XY:

0.00000794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000290

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000276

AC:

AN:

1448510

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

718748

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33022

American (AMR)

AF:

0.00

AC:

AN:

43386

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25642

East Asian (EAS)

AF:

0.00

AC:

AN:

39262

South Asian (SAS)

AF:

0.00

AC:

AN:

85122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0000362

AC:

AN:

1103916

Other (OTH)

AF:

0.00

AC:

AN:

59710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000829

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

Eigen

Benign

0.11

Eigen_PC

Benign

0.040

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.61

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.54

MetaSVM

Benign

-1.1

PhyloP100

3.3

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.8

REVEL

Benign

0.19

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.42

MutPred

0.56

Gain of catalytic residue at F146 (P = 0.0068)

MVP

0.72

MPC

0.35

ClinPred

0.91

GERP RS

3.4

Varity_R

0.51

gMVP

0.58

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over