Genetic Variant GRK4:c.149-1818C>T (chr4-2986909-C-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_182982.3(GRK4):c.149-1818C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 300,206 control chromosomes in the GnomAD database, including 26,715 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 0.45 ( 16421 hom., cov: 31)

Exomes 𝑓: 0.36 ( 10294 hom. )

Consequence

GRK4
NM_182982.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.33

Publications

13 publications found

Variant links:

Genes affected

GRK4 (HGNC:4543): (G protein-coupled receptor kinase 4) 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 its deactivation. This gene has been linked to both genetic and acquired hypertension. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

GRK4 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK4	NM_182982.3 link	c.149-1818C>T		intron_variant	Intron 2 of 15	ENST00000398052.9	NP_892027.2	P32298-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GRK4	ENST00000398052.9 link	c.149-1818C>T	intron_variant	Intron 2 of 15	1	NM_182982.3	ENSP00000381129.4	P32298-1
GRK4	ENST00000345167.10 link	c.53-1818C>T	intron_variant	Intron 1 of 14	1		ENSP00000264764.8	P32298-2
GRK4	ENST00000504933.1 link	c.149-1818C>T	intron_variant	Intron 2 of 14	1		ENSP00000427445.1	P32298-4
GRK4	ENST00000398051.8 link	c.53-1818C>T	intron_variant	Intron 1 of 13	1		ENSP00000381128.4	P32298-3

Frequencies

GnomAD3 genomes

AF:

0.451

AC:

68420

AN:

151746

Hom.:

16394

Cov.:

show subpopulations

Gnomad AFR

AF:

0.601

Gnomad AMI

AF:

0.438

Gnomad AMR

AF:

0.352

Gnomad ASJ

AF:

0.373

Gnomad EAS

AF:

0.178

Gnomad SAS

AF:

0.231

Gnomad FIN

AF:

0.544

Gnomad MID

AF:

0.405

Gnomad NFE

AF:

0.409

Gnomad OTH

AF:

0.415

GnomAD4 exome

AF:

0.356

AC:

52820

AN:

148342

Hom.:

10294

AF XY:

0.339

AC XY:

28297

AN XY:

83552

show subpopulations

African (AFR)

AF:

0.599

AC:

2333

AN:

3894

American (AMR)

AF:

0.355

AC:

2310

AN:

6508

Ashkenazi Jewish (ASJ)

AF:

0.368

AC:

1348

AN:

3666

East Asian (EAS)

AF:

0.173

AC:

1078

AN:

6216

South Asian (SAS)

AF:

0.221

AC:

6907

AN:

31320

European-Finnish (FIN)

AF:

0.504

AC:

3484

AN:

6908

Middle Eastern (MID)

AF:

0.419

AC:

823

AN:

1966

European-Non Finnish (NFE)

AF:

0.394

AC:

31875

AN:

80870

Other (OTH)

AF:

0.381

AC:

2662

AN:

6994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1482

2963

4445

5926

7408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

218

436

654

872

1090

<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:

0.451

AC:

68491

AN:

151864

Hom.:

16421

Cov.:

AF XY:

0.450

AC XY:

33377

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.601

AC:

24869

AN:

41366

American (AMR)

AF:

0.352

AC:

5374

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.373

AC:

1291

AN:

3462

East Asian (EAS)

AF:

0.177

AC:

915

AN:

5174

South Asian (SAS)

AF:

0.231

AC:

1111

AN:

4810

European-Finnish (FIN)

AF:

0.544

AC:

5740

AN:

10542

Middle Eastern (MID)

AF:

0.415

AC:

122

AN:

294

European-Non Finnish (NFE)

AF:

0.409

AC:

27807

AN:

67946

Other (OTH)

AF:

0.411

AC:

863

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1837

3674

5511

7348

9185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

602

1204

1806

2408

3010

<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:

0.414

Hom.:

6754

Bravo

AF:

0.445

Asia WGS

AF:

0.250

AC:

871

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

1.1

(source)

DANN

Benign

0.16

PhyloP100

-1.3

Mutation Taster

=100/0

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