NM_001619.5:c.1161-100T>G

Variant names:

• chr11-67282652-T-G
• rs3730145
• NM_001619.5:c.1161-100T>G

Variant summary

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

The NM_001619.5(GRK2):​c.1161-100T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0349 in 1,558,820 control chromosomes in the GnomAD database, including 5,868 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 0.12 (3083 hom., cov: 32)
  • Exomes 𝑓: 0.026 (2785 hom.)
• Consequence: GRK2 NM_001619.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.898
• Publications: 3 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.373 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.1161-100T>G		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.1161-100T>G		intron	N/A	ENSP00000312262.5
	GRK2	ENST00000936739.1		c.1188-100T>G		intron	N/A	ENSP00000606798.1
	GRK2	ENST00000951317.1		c.1161-100T>G		intron	N/A	ENSP00000621376.1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18300 AN: 152042 Hom.: 3073 Cov.: 32

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0521

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.0547

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0222

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0156

Gnomad OTH AF: 0.0895

GnomAD4 exome AF: 0.0256 AC: 36065 AN: 1406660 Hom.: 2785 Cov.: 25 AF XY: 0.0241 AC XY: 16862 AN XY: 700058

African (AFR) AF: 0.381 AC: 12354 AN: 32436

American (AMR) AF: 0.0305 AC: 1292 AN: 42354

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 436 AN: 24790

East Asian (EAS) AF: 0.0500 AC: 1955 AN: 39114

South Asian (SAS) AF: 0.0104 AC: 865 AN: 83126

European-Finnish (FIN) AF: 0.0165 AC: 831 AN: 50222

Middle Eastern (MID) AF: 0.0239 AC: 135 AN: 5658

European-Non Finnish (NFE) AF: 0.0150 AC: 16059 AN: 1070478

Other (OTH) AF: 0.0366 AC: 2138 AN: 58482

GnomAD4 genome AF: 0.121 AC: 18348 AN: 152160 Hom.: 3083 Cov.: 32 AF XY: 0.117 AC XY: 8678 AN XY: 74402

African (AFR) AF: 0.378 AC: 15668 AN: 41476

American (AMR) AF: 0.0519 AC: 794 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3472

East Asian (EAS) AF: 0.0546 AC: 283 AN: 5182

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4828

European-Finnish (FIN) AF: 0.0222 AC: 236 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0156 AC: 1063 AN: 67982

Other (OTH) AF: 0.0885 AC: 187 AN: 2112

Alfa AF: 0.100 Hom.: 433

Bravo AF: 0.133

Asia WGS AF: 0.0360 AC: 126 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.96
DANN	Benign	0.74
PhyloP100		-0.90
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: rs3730145; hg19: chr11-67050123; COSMIC: COSV57952720; COSMIC: COSV57952720;