Genetic Variant GRK2:c.1161-100T>G (chr11-67282652-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.898

Publications

3 publications found

Variant links:

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

GRK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Sel.	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	P25098

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GRK2	ENST00000308595.10	TSL:1 MANE Select	c.1161-100T>G	intron	N/A	ENSP00000312262.5	P25098
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.:

show subpopulations

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.:

AF XY:

0.0241

AC XY:

16862

AN XY:

700058

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1671

3342

5014

6685

8356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

784

1568

2352

3136

3920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.121

AC:

18348

AN:

152160

Hom.:

3083

Cov.:

AF XY:

0.117

AC XY:

8678

AN XY:

74402

show subpopulations

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:

AN:

3472

East Asian (EAS)

AF:

0.0546

AC:

283

AN:

5182

South Asian (SAS)

AF:

0.00932

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0222

AC:

236

AN:

10610

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0156

AC:

1063

AN:

67982

Other (OTH)

AF:

0.0885

AC:

187

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

644

1288

1931

2575

3219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

DANN

Benign

0.74

PhyloP100

-0.90

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over