rs4370946

Positions:

• chr11-67285667-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GRK2	NM_001619.5	c.*217C>T		3_prime_UTR_variant	21/21	ENST00000308595.10	NP_001610.2
GRK2	XM_011544773.2	c.*217C>T		3_prime_UTR_variant	21/21		XP_011543075.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRK2	ENST00000308595.10	c.*217C>T		3_prime_UTR_variant	21/21	1	NM_001619.5	ENSP00000312262	P1
GRK2	ENST00000526285.1	c.1096-726C>T		intron_variant		5		ENSP00000434126
GRK2	ENST00000416281.6	n.3605C>T		non_coding_transcript_exon_variant	17/17	2
GRK2	ENST00000529738.1	n.184-389C>T		intron_variant, non_coding_transcript_variant		2

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

Gnomad4 AFR exome AF: 0.291

Gnomad4 AMR exome AF: 0.0216

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000187

Gnomad4 SAS exome AF: 0.000546

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000631

Gnomad4 OTH exome AF: 0.0221

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

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.0340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0577

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.39
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs4370946; hg19: chr11-67053138;