3-141780494-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_139209.3(GRK7):c.733A>G(p.Lys245Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GRK7 NM_139209.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

Genes affected

GRK7 (HGNC:17031): (G protein-coupled receptor kinase 7) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. It is specifically expressed in the retina and the encoded protein has been shown to phosphorylate cone opsins and initiate their deactivation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRK7	NM_139209.3	c.733A>G	p.Lys245Glu	missense_variant	4/6	ENST00000682958.1
GRK7	XM_047447449.1	c.733A>G	p.Lys245Glu	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK7	ENST00000682958.1	c.733A>G	p.Lys245Glu	missense_variant	4/6		NM_139209.3	P1
GRK7	ENST00000264952.2	c.733A>G	p.Lys245Glu	missense_variant	2/4	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

The c.733A>G (p.K245E) alteration is located in exon 2 (coding exon 2) of the GRK7 gene. This alteration results from a A to G substitution at nucleotide position 733, causing the lysine (K) at amino acid position 245 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.093
Eigen_PC	Benign	-0.074
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.23
Sift	Uncertain	0.017	D
Sift4G	Benign	0.078	T
Polyphen		0.70	P
Vest4		0.46
MutPred		0.53		Loss of methylation at K245 (P = 0.0106);
MVP		0.85
MPC		0.77
ClinPred		0.97	D
GERP RS		2.7
Varity_R		0.45
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-141499336;