NM_182982.3:c.193C>G

Variant names:

• chr4-2988771-C-G
• rs372027080
• NM_182982.3:c.193C>G

Variant summary

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

The NM_182982.3(GRK4):​c.193C>G​(p.Arg65Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,900 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R65L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GRK4 NM_182982.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.25

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]

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 rank	MANE	Protein	UniProt
GRK4	NM_182982.3	c.193C>G	p.Arg65Gly	missense_variant	Exon 3 of 16	ENST00000398052.9	NP_892027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK4	ENST00000398052.9	c.193C>G	p.Arg65Gly	missense_variant	Exon 3 of 16	1	NM_182982.3	ENSP00000381129.4
GRK4	ENST00000345167.10	c.97C>G	p.Arg33Gly	missense_variant	Exon 2 of 15	1		ENSP00000264764.8
GRK4	ENST00000504933.1	c.193C>G	p.Arg65Gly	missense_variant	Exon 3 of 15	1		ENSP00000427445.1
GRK4	ENST00000398051.8	c.97C>G	p.Arg33Gly	missense_variant	Exon 2 of 14	1		ENSP00000381128.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460900 Hom.: 0 Cov.: 28 AF XY: 0.00000275 AC XY: 2 AN XY: 726806

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	.;T;.;.
Eigen	Benign	-0.031
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.2	.;L;.;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.077
Sift	Benign	0.16	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.0050	B;B;B;B
Vest4		0.18
MutPred		0.62		.;Loss of MoRF binding (P = 0.0282);.;Loss of MoRF binding (P = 0.0282);
MVP		0.48
MPC		0.10
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.46
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: -44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs372027080; hg19: chr4-2990498;