Genetic Variant GRK5:p.Arg304His (chr10-119436823-G-A) – 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.911G>A(p.Arg304His) variant causes a missense change. The variant allele was found at a frequency of 0.107 in 1,608,038 control chromosomes in the GnomAD database, including 10,752 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.082 ( 762 hom., cov: 33)

Exomes 𝑓: 0.11 ( 9990 hom. )

Consequence

GRK5
NM_005308.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.11

Publications

34 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=0.0016897321).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK5	NM_005308.3 link	c.911G>A	p.Arg304His	missense_variant	Exon 9 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.911G>A	p.Arg304His	missense_variant	Exon 9 of 16	1	NM_005308.3	ENSP00000376609.2		P34947

Frequencies

GnomAD3 genomes

AF:

0.0818

AC:

12438

AN:

152096

Hom.:

762

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0198

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.0830

Gnomad ASJ

AF:

0.0556

Gnomad EAS

AF:

0.273

Gnomad SAS

AF:

0.174

Gnomad FIN

AF:

0.0575

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.0718

GnomAD2 exomes

AF:

0.109

AC:

26723

AN:

246198

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.0207

Gnomad AMR exome

AF:

0.0956

Gnomad ASJ exome

AF:

0.0574

Gnomad EAS exome

AF:

0.264

Gnomad FIN exome

AF:

0.0587

Gnomad NFE exome

AF:

0.0987

Gnomad OTH exome

AF:

0.0933

GnomAD4 exome

AF:

0.110

AC:

159992

AN:

1455824

Hom.:

9990

Cov.:

AF XY:

0.111

AC XY:

80554

AN XY:

723562

show subpopulations

African (AFR)

AF:

0.0159

AC:

530

AN:

33382

American (AMR)

AF:

0.0923

AC:

4094

AN:

44342

Ashkenazi Jewish (ASJ)

AF:

0.0573

AC:

1470

AN:

25664

East Asian (EAS)

AF:

0.256

AC:

10132

AN:

39612

South Asian (SAS)

AF:

0.163

AC:

13959

AN:

85470

European-Finnish (FIN)

AF:

0.0603

AC:

3201

AN:

53128

Middle Eastern (MID)

AF:

0.0579

AC:

331

AN:

5718

European-Non Finnish (NFE)

AF:

0.108

AC:

119755

AN:

1108404

Other (OTH)

AF:

0.108

AC:

6520

AN:

60104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

7456

14912

22369

29825

37281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4498

8996

13494

17992

22490

<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:

0.0818

AC:

12445

AN:

152214

Hom.:

762

Cov.:

AF XY:

0.0817

AC XY:

6079

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0198

AC:

824

AN:

41564

American (AMR)

AF:

0.0831

AC:

1271

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0556

AC:

193

AN:

3470

East Asian (EAS)

AF:

0.273

AC:

1402

AN:

5136

South Asian (SAS)

AF:

0.174

AC:

838

AN:

4818

European-Finnish (FIN)

AF:

0.0575

AC:

610

AN:

10606

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.104

AC:

7081

AN:

68006

Other (OTH)

AF:

0.0725

AC:

153

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

582

1164

1745

2327

2909

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0971

Hom.:

2777

Bravo

AF:

0.0795

TwinsUK

AF:

0.110

AC:

408

ALSPAC

AF:

0.102

AC:

395

ESP6500AA

AF:

0.0227

AC:

100

ESP6500EA

AF:

0.0998

AC:

858

ExAC

AF:

0.107

AC:

13035

Asia WGS

AF:

0.155

AC:

539

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.044

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.57

PhyloP100

4.1

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.058

Sift

Uncertain

0.021

Sift4G

Benign

0.11

Polyphen

0.068

Vest4

0.098

MPC

1.0

ClinPred

0.043

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.28

Mutation Taster

=69/31

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