rs4930416

Variant names:

• chr11-67278107-A-C
• rs4930416
• NM_001619.5:c.190+759A>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.190+759A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.037 in 152,206 control chromosomes in the GnomAD database, including 438 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 0.037 (438 hom., cov: 33)
• Consequence: GRK2 NM_001619.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0590
• Publications: 6 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRK2	NM_001619.5	c.190+759A>C		intron_variant	Intron 2 of 20	ENST00000308595.10	NP_001610.2
GRK2	XM_011544773.2	c.100+759A>C		intron_variant	Intron 2 of 20		XP_011543075.1
GRK2	XR_007062455.1	n.417+759A>C		intron_variant	Intron 2 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRK2	ENST00000308595.10	c.190+759A>C		intron_variant	Intron 2 of 20	1	NM_001619.5	ENSP00000312262.5
GRK2	ENST00000526285.1	c.190+759A>C		intron_variant	Intron 2 of 13	5		ENSP00000434126.1
GRK2	ENST00000416281.6	n.812+759A>C		intron_variant	Intron 1 of 16	2
GRK2	ENST00000530291.5	n.148+759A>C		intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5629 AN: 152088 Hom.: 437 Cov.: 33

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.0243

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.0363

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0370 AC: 5633 AN: 152206 Hom.: 438 Cov.: 33 AF XY: 0.0387 AC XY: 2880 AN XY: 74422

African (AFR) AF: 0.0558 AC: 2318 AN: 41518

American (AMR) AF: 0.183 AC: 2804 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.0241 AC: 125 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10604

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00385 AC: 262 AN: 67990

Other (OTH) AF: 0.0359 AC: 76 AN: 2116

Alfa AF: 0.0241 Hom.: 31

Bravo AF: 0.0552

Asia WGS AF: 0.0270 AC: 92 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.60
PhyloP100		-0.059
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: rs4930416; hg19: chr11-67045578;