4-186233719-T-C

Position:

• chr4-186233719-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000892.5(KLKB1):​c.222-233T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,260 control chromosomes in the GnomAD database, including 1,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.13 (1512 hom., cov: 33)
• Consequence: KLKB1 NM_000892.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.858

Genes affected

KLKB1 (HGNC:6371): (kallikrein B1) This gene encodes a glycoprotein that participates in the surface-dependent activation of blood coagulation, fibrinolysis, kinin generation and inflammation. The encoded preproprotein present in plasma as a non-covalent complex with high molecular weight kininogen undergoes proteolytic processing mediated by activated coagulation factor XII to generate a disulfide-linked, heterodimeric serine protease comprised of heavy and light chains. Certain mutations in this gene cause prekallikrein deficiency. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-186233719-T-C is Benign according to our data. Variant chr4-186233719-T-C is described in ClinVar as [Benign]. Clinvar id is 1275106.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLKB1	NM_000892.5	c.222-233T>C		intron_variant		ENST00000264690.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLKB1	ENST00000264690.11	c.222-233T>C		intron_variant		1	NM_000892.5	P1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19076 AN: 152142 Hom.: 1510 Cov.: 33

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.162

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

GnomAD4 genome AF: 0.125 AC: 19075 AN: 152260 Hom.: 1512 Cov.: 33 AF XY: 0.122 AC XY: 9120 AN XY: 74450

Gnomad4 AFR AF: 0.0331

Gnomad4 AMR AF: 0.134

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.175

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.162

Alfa AF: 0.142 Hom.: 261

Bravo AF: 0.125

Asia WGS AF: 0.147 AC: 513 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.9
DANN	Benign	0.39

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

LitVar

Other links and lift over

dbSNP: rs2304596; hg19: chr4-187154873;