4-186258056-T-C

Position:

• chr4-186258056-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001318394.2(KLKB1):​c.1507T>C​(p.Trp503Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 1,613,544 control chromosomes in the GnomAD database, including 376,244 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35897 hom., cov: 32)
  • Exomes 𝑓: 0.68 (340347 hom.)
• Consequence: KLKB1 NM_001318394.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.63

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]

ENSG00000290316 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.5759297E-7).
• BP6: Variant 4-186258056-T-C is Benign according to our data. Variant chr4-186258056-T-C is described in ClinVar as [Benign]. Clinvar id is 1273364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186258056-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLKB1	NM_000892.5	c.1761T>C	p.Asn587Asn	synonymous_variant	15/15	ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11	c.1761T>C	p.Asn587Asn	synonymous_variant	15/15	1	NM_000892.5	ENSP00000264690.6
ENSG00000290316	ENST00000511608.5	c.1902T>C	p.Asn634Asn	synonymous_variant	15/15	5		ENSP00000426629.1
KLKB1	ENST00000511406.5	n.1822T>C		non_coding_transcript_exon_variant	15/15	1
KLKB1	ENST00000513864.2	c.1507T>C	p.Trp503Arg	missense_variant	15/15	2		ENSP00000424469.2

Frequencies

GnomAD3 genomes AF: 0.685 AC: 104027 AN: 151898 Hom.: 35864 Cov.: 32

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.795

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.700

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.687

Gnomad OTH AF: 0.704

GnomAD3 exomes AF: 0.676 AC: 169885 AN: 251398 Hom.: 58599 AF XY: 0.663 AC XY: 90008 AN XY: 135856

Gnomad AFR exome AF: 0.656

Gnomad AMR exome AF: 0.727

Gnomad ASJ exome AF: 0.666

Gnomad EAS exome AF: 0.859

Gnomad SAS exome AF: 0.478

Gnomad FIN exome AF: 0.696

Gnomad NFE exome AF: 0.682

Gnomad OTH exome AF: 0.698

GnomAD4 exome AF: 0.679 AC: 992924 AN: 1461528 Hom.: 340347 Cov.: 53 AF XY: 0.672 AC XY: 488858 AN XY: 727082

Gnomad4 AFR exome AF: 0.659

Gnomad4 AMR exome AF: 0.725

Gnomad4 ASJ exome AF: 0.666

Gnomad4 EAS exome AF: 0.860

Gnomad4 SAS exome AF: 0.478

Gnomad4 FIN exome AF: 0.697

Gnomad4 NFE exome AF: 0.686

Gnomad4 OTH exome AF: 0.691

GnomAD4 genome AF: 0.685 AC: 104113 AN: 152016 Hom.: 35897 Cov.: 32 AF XY: 0.682 AC XY: 50692 AN XY: 74286

Gnomad4 AFR AF: 0.666

Gnomad4 AMR AF: 0.711

Gnomad4 ASJ AF: 0.672

Gnomad4 EAS AF: 0.857

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.700

Gnomad4 NFE AF: 0.687

Gnomad4 OTH AF: 0.706

Alfa AF: 0.683 Hom.: 84252

Bravo AF: 0.692

TwinsUK AF: 0.687 AC: 2549

ALSPAC AF: 0.675 AC: 2601

ESP6500AA AF: 0.661 AC: 2914

ESP6500EA AF: 0.687 AC: 5908

ExAC AF: 0.668 AC: 81112

Asia WGS AF: 0.665 AC: 2314 AN: 3478

EpiCase AF: 0.679

EpiControl AF: 0.683

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0030
DANN	Benign	0.28
DEOGEN2	Benign	0.068	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	8.6e-7	T
MetaSVM	Benign	-0.93	T
REVEL	Benign	0.28
Sift4G	Benign	0.14	T
Vest4		0.031
ClinPred		0.022	T
GERP RS		-12

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: rs925453; hg19: chr4-187179210; COSMIC: COSV52994369;