NM_001619.5:c.1791+12G>A

Variant names:

• chr11-67284995-G-A
• rs10896164
• NM_001619.5:c.1791+12G>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.1791+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.899 in 1,612,232 control chromosomes in the GnomAD database, including 667,488 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 0.75 (47745 hom., cov: 32)
  • Exomes 𝑓: 0.91 (619743 hom.)
• Consequence: GRK2 NM_001619.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365
• Publications: 12 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.935 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK2	NM_001619.5	MANE Select	c.1791+12G>A		intron	N/A	NP_001610.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK2	ENST00000308595.10	TSL:1 MANE Select	c.1791+12G>A		intron	N/A	ENSP00000312262.5
	GRK2	ENST00000524899.1	TSL:3	n.252G>A		non_coding_transcript_exon	Exon 2 of 3
	GRK2	ENST00000527176.5	TSL:2	n.828G>A		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.753 AC: 114394 AN: 151970 Hom.: 47740 Cov.: 32

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.963

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.938

Gnomad EAS AF: 0.823

Gnomad SAS AF: 0.937

Gnomad FIN AF: 0.891

Gnomad MID AF: 0.877

Gnomad NFE AF: 0.941

Gnomad OTH AF: 0.800

GnomAD2 exomes AF: 0.836 AC: 206682 AN: 247118 AF XY: 0.862

Gnomad AFR exome AF: 0.367

Gnomad AMR exome AF: 0.556

Gnomad ASJ exome AF: 0.937

Gnomad EAS exome AF: 0.815

Gnomad FIN exome AF: 0.896

Gnomad NFE exome AF: 0.942

Gnomad OTH exome AF: 0.868

GnomAD4 exome AF: 0.914 AC: 1334684 AN: 1460144 Hom.: 619743 Cov.: 72 AF XY: 0.919 AC XY: 667219 AN XY: 726398

African (AFR) AF: 0.351 AC: 11731 AN: 33464

American (AMR) AF: 0.570 AC: 25454 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 24370 AN: 26108

East Asian (EAS) AF: 0.818 AC: 32456 AN: 39686

South Asian (SAS) AF: 0.939 AC: 81003 AN: 86240

European-Finnish (FIN) AF: 0.897 AC: 46777 AN: 52170

Middle Eastern (MID) AF: 0.888 AC: 5082 AN: 5722

European-Non Finnish (NFE) AF: 0.948 AC: 1054260 AN: 1111778

Other (OTH) AF: 0.887 AC: 53551 AN: 60346

GnomAD4 genome AF: 0.752 AC: 114426 AN: 152088 Hom.: 47745 Cov.: 32 AF XY: 0.754 AC XY: 56087 AN XY: 74360

African (AFR) AF: 0.373 AC: 15441 AN: 41442

American (AMR) AF: 0.701 AC: 10712 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.938 AC: 3255 AN: 3472

East Asian (EAS) AF: 0.823 AC: 4242 AN: 5156

South Asian (SAS) AF: 0.937 AC: 4518 AN: 4824

European-Finnish (FIN) AF: 0.891 AC: 9453 AN: 10610

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.941 AC: 63978 AN: 67980

Other (OTH) AF: 0.801 AC: 1694 AN: 2114

Alfa AF: 0.847 Hom.: 6935

Bravo AF: 0.715

Asia WGS AF: 0.795 AC: 2767 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.68
PhyloP100		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=99/1	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: rs10896164; hg19: chr11-67052466; COSMIC: COSV57754572; COSMIC: COSV57754572;