dbSNP rs2230345: GRK5:p.Gln41Leu (chr10-119326585-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005308.3(GRK5):c.122A>T(p.Gln41Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,613,872 control chromosomes in the GnomAD database, including 3,290 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.086 ( 1475 hom., cov: 33)

Exomes 𝑓: 0.022 ( 1815 hom. )

Consequence

GRK5
NM_005308.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.92

Publications

100 publications found

Variant links:

Genes affected

GRK5 (HGNC:4544): (G protein-coupled receptor kinase 5) 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 the activated forms of G protein-coupled receptors thus initiating their deactivation. It has also been shown to play a role in regulating the motility of polymorphonuclear leukocytes (PMNs). [provided by RefSeq, Jul 2008]

GRK5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019470751).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK5	NM_005308.3 link	c.122A>T	p.Gln41Leu	missense_variant	Exon 2 of 16	ENST00000392870.3	NP_005299.1	P34947

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK5	ENST00000392870.3 link	c.122A>T	p.Gln41Leu	missense_variant	Exon 2 of 16	1	NM_005308.3	ENSP00000376609.2		P34947

Frequencies

GnomAD3 genomes

AF:

0.0863

AC:

13132

AN:

152150

Hom.:

1473

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0448

Gnomad ASJ

AF:

0.0274

Gnomad EAS

AF:

0.0116

Gnomad SAS

AF:

0.0681

Gnomad FIN

AF:

0.00847

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0130

Gnomad OTH

AF:

0.0765

GnomAD2 exomes

AF:

0.0375

AC:

9435

AN:

251406

AF XY:

0.0341

show subpopulations

Gnomad AFR exome

AF:

0.266

Gnomad AMR exome

AF:

0.0220

Gnomad ASJ exome

AF:

0.0230

Gnomad EAS exome

AF:

0.0110

Gnomad FIN exome

AF:

0.0101

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.0311

GnomAD4 exome

AF:

0.0225

AC:

32876

AN:

1461604

Hom.:

1815

Cov.:

AF XY:

0.0227

AC XY:

16484

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.276

AC:

9249

AN:

33456

American (AMR)

AF:

0.0249

AC:

1113

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

648

AN:

26134

East Asian (EAS)

AF:

0.00688

AC:

273

AN:

39698

South Asian (SAS)

AF:

0.0606

AC:

5226

AN:

86246

European-Finnish (FIN)

AF:

0.00962

AC:

514

AN:

53418

Middle Eastern (MID)

AF:

0.0600

AC:

346

AN:

5766

European-Non Finnish (NFE)

AF:

0.0119

AC:

13241

AN:

1111782

Other (OTH)

AF:

0.0375

AC:

2266

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1463

2927

4390

5854

7317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

670

1340

2010

2680

3350

<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

AF:

0.0864

AC:

13159

AN:

152268

Hom.:

1475

Cov.:

AF XY:

0.0828

AC XY:

6169

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.261

AC:

10833

AN:

41516

American (AMR)

AF:

0.0446

AC:

683

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0274

AC:

AN:

3470

East Asian (EAS)

AF:

0.0114

AC:

AN:

5180

South Asian (SAS)

AF:

0.0677

AC:

327

AN:

4828

European-Finnish (FIN)

AF:

0.00847

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0130

AC:

883

AN:

68016

Other (OTH)

AF:

0.0757

AC:

160

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

536

1071

1607

2142

2678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0245

Hom.:

184

Bravo

AF:

0.0974

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.265

AC:

1166

ESP6500EA

AF:

0.0113

AC:

ExAC

AF:

0.0430

AC:

5221

Asia WGS

AF:

0.0630

AC:

218

AN:

3478

EpiCase

AF:

0.0143

EpiControl

AF:

0.0154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.037

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.1

PhyloP100

1.9

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.10

Sift

Benign

0.10

Sift4G

Benign

0.19

Polyphen

0.0020

Vest4

0.12

MPC

0.21

ClinPred

0.037

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.63

Mutation Taster

=80/20

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over