NM_000892.5:c.1761T>C

Variant names:

• chr4-186258056-T-C
• rs925453
• NM_000892.5:c.1761T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000892.5(KLKB1):​c.1761T>C​(p.Asn587Asn) variant causes a synonymous 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. 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_000892.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.63
• Publications: 45 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 -21 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 VariationId is 1273364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.63 with no splicing effect.
• 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 rank	MANE	Protein	UniProt
KLKB1	NM_000892.5	c.1761T>C	p.Asn587Asn	synonymous_variant	Exon 15 of 15	ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11	c.1761T>C	p.Asn587Asn	synonymous_variant	Exon 15 of 15	1	NM_000892.5	ENSP00000264690.6
ENSG00000290316	ENST00000511608.5	c.1902T>C	p.Asn634Asn	synonymous_variant	Exon 15 of 15	5		ENSP00000426629.1

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

GnomAD2 exomes AF: 0.676 AC: 169885 AN: 251398 AF XY: 0.663

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 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

African (AFR) AF: 0.659 AC: 22066 AN: 33462

American (AMR) AF: 0.725 AC: 32399 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 17402 AN: 26128

East Asian (EAS) AF: 0.860 AC: 34155 AN: 39700

South Asian (SAS) AF: 0.478 AC: 41266 AN: 86246

European-Finnish (FIN) AF: 0.697 AC: 37256 AN: 53420

Middle Eastern (MID) AF: 0.651 AC: 3752 AN: 5766

European-Non Finnish (NFE) AF: 0.686 AC: 762886 AN: 1111714

Other (OTH) AF: 0.691 AC: 41742 AN: 60374

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

African (AFR) AF: 0.666 AC: 27585 AN: 41430

American (AMR) AF: 0.711 AC: 10857 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.672 AC: 2334 AN: 3472

East Asian (EAS) AF: 0.857 AC: 4425 AN: 5164

South Asian (SAS) AF: 0.492 AC: 2372 AN: 4824

European-Finnish (FIN) AF: 0.700 AC: 7387 AN: 10546

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.687 AC: 46722 AN: 67988

Other (OTH) AF: 0.706 AC: 1488 AN: 2108

Alfa AF: 0.683 Hom.: 123394

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		-3.6
REVEL	Benign	0.28
Sift4G	Benign	0.14	T
Vest4		0.031
ClinPred		0.022	T
GERP RS		-12
Mutation Taster		=99/1	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: rs925453; hg19: chr4-187179210; COSMIC: COSV52994369;