rs4370946

Variant names:

• chr11-67285667-C-T
• rs4370946
• NM_001619.5:c.*217C>T

Variant summary

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

The NM_001619.5(GRK2):​c.*217C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 560,094 control chromosomes in the GnomAD database, including 2,426 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 0.087 (1949 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (477 hom.)
• Consequence: GRK2 NM_001619.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.297 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK2	NM_001619.5	MANE Select	c.*217C>T		3_prime_UTR	Exon 21 of 21	NP_001610.2	P25098

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK2	ENST00000308595.10	TSL:1 MANE Select	c.*217C>T		3_prime_UTR	Exon 21 of 21	ENSP00000312262.5	P25098
	GRK2	ENST00000936739.1		c.*217C>T		3_prime_UTR	Exon 21 of 21	ENSP00000606798.1
	GRK2	ENST00000951317.1		c.*217C>T		3_prime_UTR	Exon 21 of 21	ENSP00000621376.1

Frequencies

GnomAD3 genomes AF: 0.0870 AC: 13242 AN: 152130 Hom.: 1947 Cov.: 33

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0583

GnomAD4 exome AF: 0.00966 AC: 3939 AN: 407846 Hom.: 477 Cov.: 5 AF XY: 0.00808 AC XY: 1716 AN XY: 212256

African (AFR) AF: 0.291 AC: 2958 AN: 10182

American (AMR) AF: 0.0216 AC: 260 AN: 12024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12448

East Asian (EAS) AF: 0.000187 AC: 5 AN: 26714

South Asian (SAS) AF: 0.000546 AC: 19 AN: 34830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27684

Middle Eastern (MID) AF: 0.00660 AC: 12 AN: 1818

European-Non Finnish (NFE) AF: 0.000631 AC: 163 AN: 258496

Other (OTH) AF: 0.0221 AC: 522 AN: 23650

GnomAD4 genome AF: 0.0871 AC: 13262 AN: 152248 Hom.: 1949 Cov.: 33 AF XY: 0.0832 AC XY: 6193 AN XY: 74428

African (AFR) AF: 0.302 AC: 12535 AN: 41518

American (AMR) AF: 0.0340 AC: 520 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68008

Other (OTH) AF: 0.0577 AC: 122 AN: 2114

Alfa AF: 0.0660 Hom.: 145

Bravo AF: 0.0973

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.39
DANN	Benign	0.74
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	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: rs4370946; hg19: chr11-67053138;