rs3730309

Variant names:

• chr11-67279777-T-C
• rs3730309
• NM_001619.5:c.442-62T>C

Variant summary

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

The NM_001619.5(GRK2):​c.442-62T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0162 in 1,611,864 control chromosomes in the GnomAD database, including 3,722 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 0.088 (2002 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (1720 hom.)
• Consequence: GRK2 NM_001619.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.74
• Publications: 2 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK2	NM_001619.5	c.442-62T>C		intron_variant	Intron 5 of 20	ENST00000308595.10	NP_001610.2
GRK2	XM_011544773.2	c.352-62T>C		intron_variant	Intron 5 of 20		XP_011543075.1
GRK2	XR_007062455.1	n.669-62T>C		intron_variant	Intron 5 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK2	ENST00000308595.10	c.442-62T>C		intron_variant	Intron 5 of 20	1	NM_001619.5	ENSP00000312262.5
GRK2	ENST00000526285.1	c.442-62T>C		intron_variant	Intron 5 of 13	5		ENSP00000434126.1
GRK2	ENST00000416281.6	n.1064-62T>C		intron_variant	Intron 4 of 16	2
GRK2	ENST00000529738.1	n.122-62T>C		intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0882 AC: 13396 AN: 151860 Hom.: 2000 Cov.: 33

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0348

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.0601

GnomAD4 exome AF: 0.00865 AC: 12633 AN: 1459886 Hom.: 1720 Cov.: 31 AF XY: 0.00740 AC XY: 5376 AN XY: 726348

African (AFR) AF: 0.307 AC: 10273 AN: 33444

American (AMR) AF: 0.0165 AC: 739 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.000534 AC: 46 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53184

Middle Eastern (MID) AF: 0.00919 AC: 53 AN: 5766

European-Non Finnish (NFE) AF: 0.000382 AC: 424 AN: 1110424

Other (OTH) AF: 0.0182 AC: 1096 AN: 60328

GnomAD4 genome AF: 0.0883 AC: 13417 AN: 151978 Hom.: 2002 Cov.: 33 AF XY: 0.0843 AC XY: 6265 AN XY: 74282

African (AFR) AF: 0.306 AC: 12681 AN: 41408

American (AMR) AF: 0.0346 AC: 529 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 67972

Other (OTH) AF: 0.0595 AC: 125 AN: 2102

Alfa AF: 0.0668 Hom.: 149

Bravo AF: 0.0985

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.020
DANN	Benign	0.59
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3730309; hg19: chr11-67047248;