rs17098707

chr10-119326585-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005308.3(GRK5):c.122A>T(p.Gln41Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,613,872 control chromosomes in the GnomAD database, including 3,290 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.086 (1475 hom., cov: 33)
  • Exomes 𝑓: 0.022 (1815 hom.)
• Consequence: GRK5 NM_005308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92

Genes affected

GRK5 (HGNC:4544): (G protein-coupled receptor kinase 5) 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 their deactivation. It has also been shown to play a role in regulating the motility of polymorphonuclear leukocytes (PMNs). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019470751).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRK5	NM_005308.3	c.122A>T	p.Gln41Leu	missense_variant	2/16	ENST00000392870.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK5	ENST00000392870.3	c.122A>T	p.Gln41Leu	missense_variant	2/16	1	NM_005308.3	P1

Frequencies

GnomAD3 genomes AF: 0.0863 AC: 13132 AN: 152150 Hom.: 1473 Cov.: 33

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0448

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0681

Gnomad FIN AF: 0.00847

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0130

Gnomad OTH AF: 0.0765

GnomAD3 exomes AF: 0.0375 AC: 9435 AN: 251406 Hom.: 709 AF XY: 0.0341 AC XY: 4628 AN XY: 135884

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.0230

Gnomad EAS exome AF: 0.0110

Gnomad SAS exome AF: 0.0626

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0225 AC: 32876 AN: 1461604 Hom.: 1815 Cov.: 31 AF XY: 0.0227 AC XY: 16484 AN XY: 727148

Gnomad4 AFR exome AF: 0.276

Gnomad4 AMR exome AF: 0.0249

Gnomad4 ASJ exome AF: 0.0248

Gnomad4 EAS exome AF: 0.00688

Gnomad4 SAS exome AF: 0.0606

Gnomad4 FIN exome AF: 0.00962

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0375

GnomAD4 genome AF: 0.0864 AC: 13159 AN: 152268 Hom.: 1475 Cov.: 33 AF XY: 0.0828 AC XY: 6169 AN XY: 74464

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.0446

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.0677

Gnomad4 FIN AF: 0.00847

Gnomad4 NFE AF: 0.0130

Gnomad4 OTH AF: 0.0757

Alfa AF: 0.0245 Hom.: 184

Bravo AF: 0.0974

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.265 AC: 1166

ESP6500EA AF: 0.0113 AC: 97

ExAC AF: 0.0430 AC: 5221

Asia WGS AF: 0.0630 AC: 218 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.0076	P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.10
Sift	Benign	0.10	T
Sift4G	Benign	0.19	T
Polyphen		0.0020	B
Vest4		0.12
MPC		0.21
ClinPred		0.037	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.63

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

LitVar

Other links and lift over

dbSNP: rs2230345; hg19: chr10-121086097; COSMIC: COSV67310450; COSMIC: COSV67310450;