10-119436767-G-C

Position:

• chr10-119436767-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005308.3(GRK5):​c.855G>C​(p.Glu285Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GRK5 NM_005308.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.27

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRK5	NM_005308.3	c.855G>C	p.Glu285Asp	missense_variant	9/16	ENST00000392870.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK5	ENST00000392870.3	c.855G>C	p.Glu285Asp	missense_variant	9/16	1	NM_005308.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

GRK5-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2024

The GRK5 c.855G>C variant is predicted to result in the amino acid substitution p.Glu285Asp. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.013
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0067	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.17
Sift	Benign	0.097	T
Sift4G	Benign	0.10	T
Polyphen		0.018	B
Vest4		0.53
MutPred		0.71		Loss of disorder (P = 0.1174);
MVP		0.63
MPC		0.73
ClinPred		0.69	D
GERP RS		4.4
Varity_R		0.51
gMVP		0.70

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: chr10-121196279;