chr11-67271141-T-C

Variant names:

• chr11-67271141-T-C
• rs1894111
• NM_001619.5:c.113+4329T>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.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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.43
• Publications: 10 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.982 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.113+4329T>C		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.113+4329T>C		intron	N/A	ENSP00000312262.5
	GRK2	ENST00000526285.1	TSL:5	c.113+4329T>C		intron	N/A	ENSP00000434126.1
	GRK2	ENST00000530291.5	TSL:2	n.71+133T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.953 AC: 145031 AN: 152126 Hom.: 69306 Cov.: 31

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.: 87 AF XY: 0.991 AC XY: 107 AN XY: 108

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

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AF: 1.00 AC: 2 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.962 AC: 75 AN: 78

Middle Eastern (MID) AF: 1.00 AC: 4 AN: 4

European-Non Finnish (NFE) AF: 1.00 AC: 66 AN: 66

Other (OTH) AF: 0.967 AC: 29 AN: 30

⚠️ 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.

GnomAD4 genome AF: 0.953 AC: 145115 AN: 152244 Hom.: 69338 Cov.: 31 AF XY: 0.952 AC XY: 70847 AN XY: 74436

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.021
DANN	Benign	0.85
PhyloP100		-2.4
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: rs1894111; hg19: chr11-67038612;