chr4-2992276-G-A

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 (★). Synonymous variant affecting the same amino acid position (i.e. R108R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GRK4
NM_182982.3 missense

Scores

19

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]

Genome browser will be placed here

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 UniProt
GRK4NM_182982.3 linkuse as main transcriptc.323G>A p.Arg108Lys missense_variant 4/16 ENST00000398052.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GRK4ENST00000398052.9 linkuse as main transcriptc.323G>A p.Arg108Lys missense_variant 4/161 NM_182982.3 P1P32298-1
GRK4ENST00000345167.10 linkuse as main transcriptc.227G>A p.Arg76Lys missense_variant 3/151 P32298-2
GRK4ENST00000504933.1 linkuse as main transcriptc.323G>A p.Arg108Lys missense_variant 4/151 P32298-4
GRK4ENST00000398051.8 linkuse as main transcriptc.227G>A p.Arg76Lys missense_variant 3/141 P32298-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000207
AC:
3
AN:
1451218
Hom.:
0
Cov.:
27
AF XY:
0.00000138
AC XY:
1
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.:
32

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 submitterclinical testingAmbry GeneticsJul 30, 2023The 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
T
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
N
LIST_S2
Benign
0.34
T;T;T;T
M_CAP
Benign
0.0011
T
MetaRNN
Benign
0.034
T;T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
-0.025
.;N;.;N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.21
T
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
T
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.

Other links and lift over

hg19: chr4-2994003; COSMIC: COSV61670598; API