22-25565293-C-G

Position:

• chr22-25565293-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000324198.11(GRK3):​c.113+140C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 429,418 control chromosomes in the GnomAD database, including 70 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.

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 32)
  • Exomes 𝑓: 0.014 (49 hom.)
• Consequence: GRK3 ENST00000324198.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.858

Genes affected

GRK3 (HGNC:290): (G protein-coupled receptor kinase 3) The beta-adrenergic receptor kinase specifically phosphorylates the agonist-occupied form of the beta-adrenergic and related G protein-coupled receptors. Overall, the beta adrenergic receptor kinase 2 has 85% amino acid similarity with beta adrenergic receptor kinase 1, with the protein kinase catalytic domain having 95% similarity. These data suggest the existence of a family of receptor kinases which may serve broadly to regulate receptor function. [provided by RefSeq, Jul 2008]

GRK3-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1691/152224) while in subpopulation NFE AF= 0.0175 (1187/67990). AF 95% confidence interval is 0.0166. There are 21 homozygotes in gnomad4. There are 753 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRK3	NM_005160.4	c.113+140C>G		intron_variant		ENST00000324198.11	NP_005151.2
GRK3-AS1	NR_183563.1	n.124G>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRK3	ENST00000324198.11	c.113+140C>G		intron_variant		1	NM_005160.4	ENSP00000317578	P1
GRK3	ENST00000455558.2	c.47+140C>G		intron_variant, NMD_transcript_variant		5		ENSP00000393688

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1693 AN: 152106 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0175

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0140 AC: 3894 AN: 277194 Hom.: 49 AF XY: 0.0135 AC XY: 2036 AN XY: 150334

Gnomad4 AFR exome AF: 0.00373

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.0276

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00582

Gnomad4 FIN exome AF: 0.00541

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0111 AC: 1691 AN: 152224 Hom.: 21 Cov.: 32 AF XY: 0.0101 AC XY: 753 AN XY: 74400

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.0274

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.0175

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00430 Hom.: 1

Bravo AF: 0.0116

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.5
DANN	Benign	0.55

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: rs41258164; hg19: chr22-25961260;