rs4253252

Variant names:

• chr4-186236304-T-G
• rs4253252
• NM_000892.5:c.329-477T>G

Variant summary

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

The NM_000892.5(KLKB1):​c.329-477T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 151,996 control chromosomes in the GnomAD database, including 24,148 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 (24148 hom., cov: 32)
• Consequence: KLKB1 NM_000892.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.691
• Publications: 21 publications found

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]

KLKB1 Gene-Disease associations (from GenCC):

• inherited prekallikrein deficiency

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

ENSG00000290316 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLKB1	NM_000892.5	c.329-477T>G		intron_variant	Intron 4 of 14	ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11	c.329-477T>G		intron_variant	Intron 4 of 14	1	NM_000892.5	ENSP00000264690.6
ENSG00000290316	ENST00000511608.5	c.470-477T>G		intron_variant	Intron 4 of 14	5		ENSP00000426629.1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84927 AN: 151878 Hom.: 24117 Cov.: 32

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.552

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

GnomAD4 genome AF: 0.559 AC: 85010 AN: 151996 Hom.: 24148 Cov.: 32 AF XY: 0.559 AC XY: 41544 AN XY: 74298

African (AFR) AF: 0.639 AC: 26490 AN: 41448

American (AMR) AF: 0.576 AC: 8800 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1541 AN: 3472

East Asian (EAS) AF: 0.680 AC: 3511 AN: 5160

South Asian (SAS) AF: 0.400 AC: 1926 AN: 4816

European-Finnish (FIN) AF: 0.583 AC: 6147 AN: 10552

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34718 AN: 67956

Other (OTH) AF: 0.554 AC: 1167 AN: 2108

Alfa AF: 0.526 Hom.: 61205

Bravo AF: 0.568

Asia WGS AF: 0.525 AC: 1826 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.81
DANN	Benign	0.57
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4253252; hg19: chr4-187157458;