5-177414338-T-C

Variant names:

• chr5-177414338-T-C
• rs2545801
• ENST00000506296.5:c.-45+9781T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000502598.5(GRK6):​c.-45+10812T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 152,136 control chromosomes in the GnomAD database, including 28,482 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 0.56 (28482 hom., cov: 32)
• Consequence: GRK6 ENST00000502598.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.198
• Publications: 33 publications found

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]

F12 Gene-Disease associations (from GenCC):

• hereditary angioedema type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, Orphanet
• congenital factor XII deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000502598.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRK6	ENST00000506296.5	TSL:5	c.-45+9781T>C		intron	N/A	ENSP00000421055.1	D6RHC7
	GRK6	ENST00000502598.5	TSL:4	c.-45+10812T>C		intron	N/A	ENSP00000422873.1	D6R9V4
	F12	ENST00000696200.1		n.78+2168A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84826 AN: 152018 Hom.: 28493 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.622

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.740

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.748

Gnomad OTH AF: 0.614

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

GnomAD4 genome AF: 0.557 AC: 84811 AN: 152136 Hom.: 28482 Cov.: 32 AF XY: 0.556 AC XY: 41312 AN XY: 74354

African (AFR) AF: 0.194 AC: 8046 AN: 41534

American (AMR) AF: 0.622 AC: 9493 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 2668 AN: 3472

East Asian (EAS) AF: 0.260 AC: 1343 AN: 5172

South Asian (SAS) AF: 0.479 AC: 2312 AN: 4822

European-Finnish (FIN) AF: 0.740 AC: 7828 AN: 10574

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.748 AC: 50821 AN: 67978

Other (OTH) AF: 0.610 AC: 1290 AN: 2114

Alfa AF: 0.678 Hom.: 112185

Bravo AF: 0.536

Asia WGS AF: 0.356 AC: 1242 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.74
PhyloP100		-0.20

Splicing

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

Other links and lift over

dbSNP: rs2545801; hg19: chr5-176841339; COSMIC: COSV53692963;