Variant 4-3013764-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_182982.3(GRK4):c.677G>A(p.Arg226Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GRK4
NM_182982.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.66

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18844855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRK4	NM_182982.3 linkuse as main transcript	c.677G>A	p.Arg226Lys	missense_variant	8/16	ENST00000398052.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK4	ENST00000398052.9 linkuse as main transcript	c.677G>A	p.Arg226Lys	missense_variant	8/16	1	NM_182982.3	P1	P32298-1
GRK4	ENST00000345167.10 linkuse as main transcript	c.581G>A	p.Arg194Lys	missense_variant	7/15	1			P32298-2
GRK4	ENST00000504933.1 linkuse as main transcript	c.677G>A	p.Arg226Lys	missense_variant	8/15	1			P32298-4
GRK4	ENST00000398051.8 linkuse as main transcript	c.581G>A	p.Arg194Lys	missense_variant	7/14	1			P32298-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461258

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726930

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.677G>A (p.R226K) alteration is located in exon 8 (coding exon 8) of the GRK4 gene. This alteration results from a G to A substitution at nucleotide position 677, causing the arginine (R) at amino acid position 226 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

.;T;.;.

Eigen

Benign

-0.028

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.53

.;N;.;N

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.8

D;D;D;D

REVEL

Benign

0.13

Sift

Benign

0.29

T;T;T;T

Sift4G

Benign

0.67

T;T;T;T

Polyphen

0.70

P;P;B;B

Vest4

0.34

MutPred

0.34

.;Gain of methylation at K221 (P = 0.0774);.;Gain of methylation at K221 (P = 0.0774);

MVP

0.61

MPC

0.075

ClinPred

0.97

GERP RS

3.8

Varity_R

0.61

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over