11-67284851-C-T

Variant names:

• chr11-67284851-C-T
• rs115867067
• NM_001619.5:c.1659C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001619.5(GRK2):​c.1659C>T​(p.Tyr553Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,612,526 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: GRK2 NM_001619.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.92
• Publications: 0 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 11-67284851-C-T is Benign according to our data. Variant chr11-67284851-C-T is described in ClinVar as [Benign]. Clinvar id is 720057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.92 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1624/152336) while in subpopulation AFR AF = 0.0376 (1562/41586). AF 95% confidence interval is 0.036. There are 33 homozygotes in GnomAd4. There are 781 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK2	NM_001619.5	c.1659C>T	p.Tyr553Tyr	synonymous_variant	Exon 19 of 21	ENST00000308595.10	NP_001610.2
GRK2	XM_011544773.2	c.1569C>T	p.Tyr523Tyr	synonymous_variant	Exon 19 of 21		XP_011543075.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK2	ENST00000308595.10	c.1659C>T	p.Tyr553Tyr	synonymous_variant	Exon 19 of 21	1	NM_001619.5	ENSP00000312262.5

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1618 AN: 152218 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00294 AC: 734 AN: 249484 AF XY: 0.00209

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000534

Gnomad OTH exome AF: 0.000984

GnomAD4 exome AF: 0.00113 AC: 1654 AN: 1460190 Hom.: 27 Cov.: 30 AF XY: 0.000933 AC XY: 678 AN XY: 726330

African (AFR) AF: 0.0406 AC: 1358 AN: 33446

American (AMR) AF: 0.00190 AC: 85 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52638

Middle Eastern (MID) AF: 0.00171 AC: 9 AN: 5276

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111850

Other (OTH) AF: 0.00214 AC: 129 AN: 60312

GnomAD4 genome AF: 0.0107 AC: 1624 AN: 152336 Hom.: 33 Cov.: 33 AF XY: 0.0105 AC XY: 781 AN XY: 74496

African (AFR) AF: 0.0376 AC: 1562 AN: 41586

American (AMR) AF: 0.00301 AC: 46 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00556 Hom.: 5

Bravo AF: 0.0124

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 31, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.1
DANN	Benign	0.81
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

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: rs115867067; hg19: chr11-67052322;