11-67266795-C-A

Variant names:

• chr11-67266795-C-A
• rs2228418
• NM_001619.5:c.96C>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001619.5(GRK2):​c.96C>A​(p.Ile32Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.884 in 1,337,718 control chromosomes in the GnomAD database, including 538,892 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 0.72 (44488 hom., cov: 29)
  • Exomes 𝑓: 0.91 (494404 hom.)
• Consequence: GRK2 NM_001619.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• Publications: 12 publications found

Genes affected

GRK2 (HGNC:289): (G protein-coupled receptor kinase 2) This gene encodes a member of the G protein-coupled receptor kinase family of proteins. The encoded protein phosphorylates the beta-adrenergic receptor as well as a wide range of other substrates including non-GPCR cell surface receptors, and cytoskeletal, mitochondrial, and transcription factor proteins. Data from rodent models supports a role for this gene in embryonic development, heart function and metabolism. Elevated expression of this gene has been observed in human patients with heart failure and Alzheimer's disease. [provided by RefSeq, Sep 2017]

GRK2 Gene-Disease associations (from GenCC):

• Jeune syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP7: Synonymous conserved (PhyloP=1.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001619.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK2	NM_001619.5	MANE Select	c.96C>A	p.Ile32Ile	synonymous	Exon 1 of 21	NP_001610.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK2	ENST00000308595.10	TSL:1 MANE Select	c.96C>A	p.Ile32Ile	synonymous	Exon 1 of 21	ENSP00000312262.5
	GRK2	ENST00000936739.1		c.96C>A	p.Ile32Ile	synonymous	Exon 1 of 21	ENSP00000606798.1
	GRK2	ENST00000951317.1		c.96C>A	p.Ile32Ile	synonymous	Exon 1 of 21	ENSP00000621376.1

Frequencies

GnomAD3 genomes AF: 0.718 AC: 108012 AN: 150366 Hom.: 44492 Cov.: 29

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.917

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.929

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.868

Gnomad NFE AF: 0.926

Gnomad OTH AF: 0.770

GnomAD2 exomes AF: 0.842 AC: 78711 AN: 93436 AF XY: 0.867

Gnomad AFR exome AF: 0.300

Gnomad AMR exome AF: 0.501

Gnomad ASJ exome AF: 0.917

Gnomad EAS exome AF: 0.765

Gnomad FIN exome AF: 0.878

Gnomad NFE exome AF: 0.926

Gnomad OTH exome AF: 0.841

GnomAD4 exome AF: 0.905 AC: 1074911 AN: 1187244 Hom.: 494404 Cov.: 29 AF XY: 0.908 AC XY: 529495 AN XY: 582910

African (AFR) AF: 0.258 AC: 6230 AN: 24138

American (AMR) AF: 0.539 AC: 10271 AN: 19060

Ashkenazi Jewish (ASJ) AF: 0.913 AC: 16294 AN: 17840

East Asian (EAS) AF: 0.768 AC: 19400 AN: 25254

South Asian (SAS) AF: 0.928 AC: 43932 AN: 47328

European-Finnish (FIN) AF: 0.878 AC: 34190 AN: 38934

Middle Eastern (MID) AF: 0.872 AC: 2948 AN: 3382

European-Non Finnish (NFE) AF: 0.934 AC: 901768 AN: 965530

Other (OTH) AF: 0.871 AC: 39878 AN: 45778

GnomAD4 genome AF: 0.718 AC: 108020 AN: 150474 Hom.: 44488 Cov.: 29 AF XY: 0.720 AC XY: 52917 AN XY: 73524

African (AFR) AF: 0.296 AC: 12184 AN: 41144

American (AMR) AF: 0.683 AC: 10373 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 3173 AN: 3460

East Asian (EAS) AF: 0.767 AC: 3809 AN: 4966

South Asian (SAS) AF: 0.929 AC: 4468 AN: 4812

European-Finnish (FIN) AF: 0.866 AC: 8819 AN: 10178

Middle Eastern (MID) AF: 0.861 AC: 248 AN: 288

European-Non Finnish (NFE) AF: 0.926 AC: 62460 AN: 67442

Other (OTH) AF: 0.771 AC: 1609 AN: 2086

Alfa AF: 0.833 Hom.: 56660

Bravo AF: 0.679

Asia WGS AF: 0.763 AC: 2435 AN: 3188

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		1.9
PromoterAI		-0.073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2228418; hg19: chr11-67034266; COSMIC: COSV57951096; COSMIC: COSV57951096;