chr4-3019675-C-G
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_182982.3(GRK4):āc.776C>Gā(p.Ala259Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
GRK4
NM_182982.3 missense
NM_182982.3 missense
Scores
4
15
Clinical Significance
Conservation
PhyloP100: 4.89
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29160702).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GRK4 | NM_182982.3 | c.776C>G | p.Ala259Gly | missense_variant | 9/16 | ENST00000398052.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GRK4 | ENST00000398052.9 | c.776C>G | p.Ala259Gly | missense_variant | 9/16 | 1 | NM_182982.3 | P1 | |
GRK4 | ENST00000345167.10 | c.680C>G | p.Ala227Gly | missense_variant | 8/15 | 1 | |||
GRK4 | ENST00000504933.1 | c.776C>G | p.Ala259Gly | missense_variant | 9/15 | 1 | |||
GRK4 | ENST00000398051.8 | c.680C>G | p.Ala227Gly | missense_variant | 8/14 | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461582Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727072
GnomAD4 exome
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1
AN:
1461582
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Cov.:
30
AF XY:
AC XY:
1
AN XY:
727072
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
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 submitter | clinical testing | Ambry Genetics | Dec 08, 2023 | The c.776C>G (p.A259G) alteration is located in exon 9 (coding exon 9) of the GRK4 gene. This alteration results from a C to G substitution at nucleotide position 776, causing the alanine (A) at amino acid position 259 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;N;.;N
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Benign
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
P;P;B;B
Vest4
MutPred
0.50
.;Gain of catalytic residue at L260 (P = 0.0871);.;Gain of catalytic residue at L260 (P = 0.0871);
MVP
MPC
0.19
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at