4-2992275-A-C

Position:

• chr4-2992275-A-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_182982.3(GRK4):​c.322A>C​(p.Arg108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,603,298 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (20 hom.)
• Consequence: GRK4 NM_182982.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.72

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-2992275-A-C is Benign according to our data. Variant chr4-2992275-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2654591.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.72 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRK4	NM_182982.3	c.322A>C	p.Arg108=	synonymous_variant	4/16	ENST00000398052.9	NP_892027.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRK4	ENST00000398052.9	c.322A>C	p.Arg108=	synonymous_variant	4/16	1	NM_182982.3	ENSP00000381129	P1
GRK4	ENST00000345167.10	c.226A>C	p.Arg76=	synonymous_variant	3/15	1		ENSP00000264764
GRK4	ENST00000504933.1	c.322A>C	p.Arg108=	synonymous_variant	4/15	1		ENSP00000427445
GRK4	ENST00000398051.8	c.226A>C	p.Arg76=	synonymous_variant	3/14	1		ENSP00000381128

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00289 AC: 726 AN: 251112 Hom.: 9 AF XY: 0.00341 AC XY: 463 AN XY: 135724

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00595

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00308

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00272 AC: 3950 AN: 1450976 Hom.: 20 Cov.: 27 AF XY: 0.00294 AC XY: 2127 AN XY: 722538

Gnomad4 AFR exome AF: 0.000422

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00861

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00579

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.00256

Gnomad4 OTH exome AF: 0.00360

GnomAD4 genome AF: 0.00219 AC: 334 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.00224 AC XY: 167 AN XY: 74482

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00301

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00317 Hom.: 2

Bravo AF: 0.00235

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

GRK4: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.50
DANN	Benign	0.46

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: rs142478577; hg19: chr4-2994002;