Genetic Variant GRK2:c.113+4329T>C (chr11-67271141-T-C) – 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.113+4329T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.953 in 152,426 control chromosomes in the GnomAD database, including 69,425 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 0.95 ( 69338 hom., cov: 31)

Exomes 𝑓: 0.98 ( 87 hom. )

Consequence

GRK2
NM_001619.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.43

Publications

10 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=-0.81).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.982 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GRK2	NM_001619.5 link	c.113+4329T>C	intron_variant	Intron 1 of 20	ENST00000308595.10	NP_001610.2
GRK2	XM_011544773.2 link	c.23+3293T>C	intron_variant	Intron 1 of 20		XP_011543075.1
GRK2	XR_007062455.1 link	n.340+4329T>C	intron_variant	Intron 1 of 16

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
GRK2	ENST00000308595.10 link	c.113+4329T>C	intron_variant	Intron 1 of 20	1	NM_001619.5	ENSP00000312262.5
GRK2	ENST00000526285.1 link	c.113+4329T>C	intron_variant	Intron 1 of 13	5		ENSP00000434126.1
GRK2	ENST00000530291.5 link	n.71+133T>C	intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.953

AC:

145031

AN:

152126

Hom.:

69306

Cov.:

show subpopulations

Gnomad AFR

AF:

0.883

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.965

Gnomad ASJ

AF:

0.996

Gnomad EAS

AF:

0.953

Gnomad SAS

AF:

0.978

Gnomad FIN

AF:

0.956

Gnomad MID

AF:

0.987

Gnomad NFE

AF:

0.989

Gnomad OTH

AF:

0.962

GnomAD4 exome

AF:

0.978

AC:

178

AN:

182

Hom.:

AF XY:

0.991

AC XY:

107

AN XY:

108

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.962

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

1.00

AC:

AN:

Other (OTH)

AF:

0.967

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000546988), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.953

AC:

145115

AN:

152244

Hom.:

69338

Cov.:

AF XY:

0.952

AC XY:

70847

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.882

AC:

36630

AN:

41524

American (AMR)

AF:

0.965

AC:

14759

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

3458

AN:

3472

East Asian (EAS)

AF:

0.952

AC:

4929

AN:

5176

South Asian (SAS)

AF:

0.979

AC:

4718

AN:

4820

European-Finnish (FIN)

AF:

0.956

AC:

10136

AN:

10604

Middle Eastern (MID)

AF:

0.986

AC:

290

AN:

294

European-Non Finnish (NFE)

AF:

0.989

AC:

67261

AN:

68038

Other (OTH)

AF:

0.961

AC:

2022

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

346

693

1039

1386

1732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.963

Hom.:

19356

Bravo

AF:

0.949

Asia WGS

AF:

0.909

AC:

3163

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.021

(source)

DANN

Benign

0.85

PhyloP100

-2.4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over