Variant 4-2992276-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_182982.3(GRK4):c.323G>A(p.Arg108Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,451,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GRK4
NM_182982.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.53

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.034069717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRK4	NM_182982.3 linkuse as main transcript	c.323G>A	p.Arg108Lys	missense_variant	4/16	ENST00000398052.9	NP_892027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRK4	ENST00000398052.9 linkuse as main transcript	c.323G>A	p.Arg108Lys	missense_variant	4/16	1	NM_182982.3	ENSP00000381129	P1	P32298-1
GRK4	ENST00000345167.10 linkuse as main transcript	c.227G>A	p.Arg76Lys	missense_variant	3/15	1		ENSP00000264764		P32298-2
GRK4	ENST00000504933.1 linkuse as main transcript	c.323G>A	p.Arg108Lys	missense_variant	4/15	1		ENSP00000427445		P32298-4
GRK4	ENST00000398051.8 linkuse as main transcript	c.227G>A	p.Arg76Lys	missense_variant	3/14	1		ENSP00000381128		P32298-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1451218

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722660

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:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Jul 30, 2023

The c.323G>A (p.R108K) alteration is located in exon 4 (coding exon 4) of the GRK4 gene. This alteration results from a G to A substitution at nucleotide position 323, causing the arginine (R) at amino acid position 108 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

0.078

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.0020

DANN

Benign

0.42

DEOGEN2

Benign

0.066

.;T;.;.

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.0083

LIST_S2

Benign

0.34

T;T;T;T

M_CAP

Benign

0.0011

MetaRNN

Benign

0.034

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.025

.;N;.;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

0.45

N;N;N;N

REVEL

Benign

0.027

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0030

B;B;B;B

Vest4

0.058

MutPred

0.53

.;Gain of methylation at R108 (P = 0.0124);.;Gain of methylation at R108 (P = 0.0124);

MVP

0.15

MPC

0.062

ClinPred

0.050

GERP RS

-11

Varity_R

0.21

gMVP

0.37

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

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