13-113667604-A-T

Position:

• chr13-113667604-A-T

Variant summary

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

The NM_002929.3(GRK1):​c.218A>T​(p.Gln73Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,266 control chromosomes in the GnomAD database, with no homozygous occurrence. 11/19 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: 6.8e-7 (0 hom.)
• Consequence: GRK1 NM_002929.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

Genes affected

GRK1 (HGNC:10013): (G protein-coupled receptor kinase 1) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates rhodopsin and initiates its deactivation. Defects in GRK1 are known to cause Oguchi disease 2 (also known as stationary night blindness Oguchi type-2). [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	Protein	UniProt
GRK1	NM_002929.3	c.218A>T	p.Gln73Leu	missense_variant	1/7	ENST00000335678.7	NP_002920.1
GRK1	XM_047430493.1	c.-6-2083A>T		intron_variant			XP_047286449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GRK1	ENST00000335678.7	c.218A>T	p.Gln73Leu	missense_variant	1/7	1	NM_002929.3	ENSP00000334876	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461266 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726932

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: 8.99e-7

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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.218A>T (p.Q73L) alteration is located in exon 1 (coding exon 1) of the GRK1 gene. This alteration results from a A to T substitution at nucleotide position 218, causing the glutamine (Q) at amino acid position 73 to be replaced by a leucine (L). 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	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.17
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.033	D
Polyphen		0.87	P
Vest4		0.52
MutPred		0.68		Gain of stability (P = 0.0485);
MVP		0.59
MPC		0.34
ClinPred		0.99	D
GERP RS		1.4
Varity_R		0.39
gMVP		0.56

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: chr13-114321919;