rs121964951

Positions:

• chr4-186257283-G-A
• chr4-186257283-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate PP5

The ENST00000264690.11(KLKB1):​c.1643G>A​(p.Cys548Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,602,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (0 hom.)
• Consequence: KLKB1 ENST00000264690.11 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.57

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 Likely_pathogenic. Variant got 9 ACMG points.

• PS1: Transcript ENST00000264690.11 (KLKB1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a helix (size 6) in uniprot entity KLKB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000264690.11
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 4-186257283-G-A is Pathogenic according to our data. Variant chr4-186257283-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12035.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}. Variant chr4-186257283-G-A is described in Lovd as [Pathogenic]. Variant chr4-186257283-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLKB1	NM_000892.5	c.1643G>A	p.Cys548Tyr	missense_variant	14/15	ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11	c.1643G>A	p.Cys548Tyr	missense_variant	14/15	1	NM_000892.5	ENSP00000264690	P1
KLKB1	ENST00000511406.5	n.1704G>A		non_coding_transcript_exon_variant	14/15	1
KLKB1	ENST00000513864.2	c.1472-738G>A		intron_variant		2		ENSP00000424469

Frequencies

GnomAD3 genomes AF: 0.000520 AC: 79 AN: 151958 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000685 AC: 171 AN: 249744 Hom.: 0 AF XY: 0.000718 AC XY: 97 AN XY: 135172

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.000993

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.000747 AC: 1084 AN: 1450332 Hom.: 0 Cov.: 27 AF XY: 0.000743 AC XY: 536 AN XY: 721764

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000992

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000473

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000884

Gnomad4 OTH exome AF: 0.000835

GnomAD4 genome AF: 0.000520 AC: 79 AN: 151958 Hom.: 0 Cov.: 33 AF XY: 0.000391 AC XY: 29 AN XY: 74212

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000852 Hom.: 0

Bravo AF: 0.000544

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000750 AC: 91

Asia WGS AF: 0.000290 AC: 1 AN: 3458

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Prekallikrein deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2003

- -

Inherited prekallikrein deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz

Dec 09, 2022

We have identified the variant NM_000892.4(KLKB1):c.1643G>A p.(Cys548Tyr) in three unrelated families, each with an index case of severe prekallikrein (PK) deficiency (Barco et al. PMID: 32202057). Family 1 comprises an index case homozygous for the above variant (<1% PK activity; 10% PK antigen; prolonged aPTT) and its heterozygous parents. The second family consists of a compound heterozygous index case carrying the above variant and the stop gained variant c.1196G>A p.(Trp399*) (<1% PK activity; 6-10% PK antigen; prolonged aPTT) and its daughter heterozygous for c.1643G>A (family first described in PMID: 8259543 as "PK Zurich"). The third case is a single compound heterozygous individual carrying the above variant and c.689T>A p.(Ile230Asn) (<1% PK activity; 9% PK antigen; prolonged aPTT) (first published in a PhD thesis: urn:nbn:de:hebis:30-67544 (in German)). Eight more cases have been reported in the literature by five authors (summarized in PMID: 32202057); some use the old nomenclature Cys529Tyr: Farac presents in her above mentioned PhD thesis two further compound heterozygous cases of Cys548Tyr (with c.451dupT and c.717_719delCTT, respectively) and one homozygous case. Dasanu et al. (PMID: 19773642) reported one, and Francois et al. (PMID: 17413767) two unrelated homozygous cases. Two other compound heterozygous cases are described by Maak et al (also with c.451dupT)(PMID: 19404525) and Lombardi et al (with c.1205G>A)(PMID: 14652634). All of these cases have in common that they have no PK activity (<1%) but, if measured, a residual antigen of 6-10% (CRM+). In addition, this variant has a global MAF of 0.03-0.08% (dbSNP) but reaches a MAF of 0.1% (GnomAD) among Europeans and Latinos, making it the most common PK deficiency-causing variant in these two collectives (Barco et al. PMID: 32202057). Based on all this, this variant is clearly pathogenic (ACMG criteria). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2017

The C548Y variant in the KLKB1 gene has been reported previously in prekallikrein deficiency, in an individual with prolonged activated partial thromboplastin time who was compound heterozygous for the C548Y variant and another variant (Lombardi et al., 2003). The C548Y variant is observed in 19/11574 (0.16%) alleles from individuals of Latino background, and in 68/66574 (0.10%) alleles from individuals of Non-Finnish European background, in the ExAC dataset (Lek et al., 2016). The C548Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret C548Y as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.93
MVP		0.98
MPC		0.71
ClinPred		0.93	D
GERP RS		5.8
gMVP		0.99

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: rs121964951; hg19: chr4-187178437;