rs2731672

Positions:

• chr5-177415473-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000506296.5(GRK6):​c.-45+10916T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.657 in 152,124 control chromosomes in the GnomAD database, including 34,232 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 0.66 (34232 hom., cov: 32)
• Consequence: GRK6 ENST00000506296.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.296

Genes affected

GRK6 (HGNC:4545): (G protein-coupled receptor kinase 6) 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 the activated forms of G protein-coupled receptors thus initiating their deactivation. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

F12 (HGNC:3530): (coagulation factor XII) This gene encodes coagulation factor XII which circulates in blood as a zymogen. This single chain zymogen is converted to a two-chain serine protease with an heavy chain (alpha-factor XIIa) and a light chain. The heavy chain contains two fibronectin-type domains, two epidermal growth factor (EGF)-like domains, a kringle domain and a proline-rich domain, whereas the light chain contains only a catalytic domain. On activation, further cleavages takes place in the heavy chain, resulting in the production of beta-factor XIIa light chain and the alpha-factor XIIa light chain becomes beta-factor XIIa heavy chain. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then to beta-factor XIIa. The active factor XIIa participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. It activates coagulation factors VII and XI. Defects in this gene do not cause any clinical symptoms and the sole effect is that whole-blood clotting time is prolonged. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRK6	ENST00000502598.5	c.-45+11947T>C		intron_variant		4
GRK6	ENST00000506296.5	c.-45+10916T>C		intron_variant		5
F12	ENST00000696200.1	n.78+1033A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99916 AN: 152006 Hom.: 34222 Cov.: 32

Gnomad AFR AF: 0.537

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.741

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.697

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.657 AC: 99964 AN: 152124 Hom.: 34232 Cov.: 32 AF XY: 0.652 AC XY: 48482 AN XY: 74368

Gnomad4 AFR AF: 0.537

Gnomad4 AMR AF: 0.660

Gnomad4 ASJ AF: 0.794

Gnomad4 EAS AF: 0.216

Gnomad4 SAS AF: 0.504

Gnomad4 FIN AF: 0.741

Gnomad4 NFE AF: 0.750

Gnomad4 OTH AF: 0.691

Alfa AF: 0.730 Hom.: 87396

Bravo AF: 0.649

Asia WGS AF: 0.395 AC: 1378 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.0
DANN	Benign	0.82

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2731672; hg19: chr5-176842474;