rs2071007

Variant names:

• chr11-67282821-G-A
• rs2071007
• NM_001619.5:c.1227+3G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001619.5(GRK2):​c.1227+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.88 in 1,606,630 control chromosomes in the GnomAD database, including 641,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.72 (45131 hom., cov: 33)
  • Exomes 𝑓: 0.90 (595897 hom.)
• Consequence: GRK2 NM_001619.5 splice_region, intron
• Scores: Splicing: ADA: 0.00006330
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 17 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK2	NM_001619.5	c.1227+3G>A		splice_region_variant, intron_variant	Intron 14 of 20	ENST00000308595.10	NP_001610.2
GRK2	XM_011544773.2	c.1137+3G>A		splice_region_variant, intron_variant	Intron 14 of 20		XP_011543075.1
GRK2	XR_007062455.1	n.1454+3G>A		splice_region_variant, intron_variant	Intron 14 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK2	ENST00000308595.10	c.1227+3G>A		splice_region_variant, intron_variant	Intron 14 of 20	1	NM_001619.5	ENSP00000312262.5

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109715 AN: 152052 Hom.: 45133 Cov.: 33

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.962

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.919

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.929

Gnomad FIN AF: 0.867

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.926

Gnomad OTH AF: 0.773

GnomAD2 exomes AF: 0.813 AC: 198129 AN: 243642 AF XY: 0.841

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.540

Gnomad ASJ exome AF: 0.919

Gnomad EAS exome AF: 0.763

Gnomad FIN exome AF: 0.878

Gnomad NFE exome AF: 0.925

Gnomad OTH exome AF: 0.849

GnomAD4 exome AF: 0.897 AC: 1304345 AN: 1454460 Hom.: 595897 Cov.: 50 AF XY: 0.902 AC XY: 652354 AN XY: 723602

African (AFR) AF: 0.283 AC: 9461 AN: 33418

American (AMR) AF: 0.555 AC: 24667 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.916 AC: 23915 AN: 26118

East Asian (EAS) AF: 0.760 AC: 30089 AN: 39578

South Asian (SAS) AF: 0.929 AC: 79938 AN: 86020

European-Finnish (FIN) AF: 0.879 AC: 42120 AN: 47902

Middle Eastern (MID) AF: 0.873 AC: 5028 AN: 5762

European-Non Finnish (NFE) AF: 0.933 AC: 1036728 AN: 1110964

Other (OTH) AF: 0.869 AC: 52399 AN: 60276

GnomAD4 genome AF: 0.721 AC: 109728 AN: 152170 Hom.: 45131 Cov.: 33 AF XY: 0.723 AC XY: 53763 AN XY: 74384

African (AFR) AF: 0.307 AC: 12719 AN: 41490

American (AMR) AF: 0.683 AC: 10448 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.919 AC: 3191 AN: 3472

East Asian (EAS) AF: 0.764 AC: 3941 AN: 5156

South Asian (SAS) AF: 0.928 AC: 4485 AN: 4832

European-Finnish (FIN) AF: 0.867 AC: 9199 AN: 10608

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.926 AC: 62982 AN: 68008

Other (OTH) AF: 0.774 AC: 1633 AN: 2110

Alfa AF: 0.866 Hom.: 69938

Bravo AF: 0.683

Asia WGS AF: 0.772 AC: 2686 AN: 3478

EpiCase AF: 0.929

EpiControl AF: 0.929

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.65
PhyloP100		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=45/55	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000063
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.020		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: rs2071007; hg19: chr11-67050292;