chr4-186257319-G-A

Position:

• chr4-186257319-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP6_Very_Strong BA1

The ENST00000264690.11(KLKB1):​c.1679G>A​(p.Arg560Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,601,918 control chromosomes in the GnomAD database, including 15,590 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2326 hom., cov: 32)
  • Exomes 𝑓: 0.12 (13264 hom.)
• Consequence: KLKB1 ENST00000264690.11 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.59

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.

• PM1: In a disulfide_bond (size 15) in uniprot entity KLKB1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in ENST00000264690.11
• BP6: Variant 4-186257319-G-A is Benign according to our data. Variant chr4-186257319-G-A is described in ClinVar as [Benign]. Clinvar id is 1297284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186257319-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLKB1	NM_000892.5	c.1679G>A	p.Arg560Gln	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.1679G>A	p.Arg560Gln	missense_variant	14/15	1	NM_000892.5	ENSP00000264690	P1
KLKB1	ENST00000511406.5	n.1740G>A		non_coding_transcript_exon_variant	14/15	1
KLKB1	ENST00000513864.2	c.1472-702G>A		intron_variant		2		ENSP00000424469

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24646 AN: 151704 Hom.: 2327 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.170

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.145

GnomAD3 exomes AF: 0.165 AC: 41154 AN: 249108 Hom.: 4163 AF XY: 0.161 AC XY: 21754 AN XY: 134826

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.306

Gnomad SAS exome AF: 0.222

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.123 AC: 178163 AN: 1450098 Hom.: 13264 Cov.: 29 AF XY: 0.125 AC XY: 89969 AN XY: 721410

Gnomad4 AFR exome AF: 0.239

Gnomad4 AMR exome AF: 0.248

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.294

Gnomad4 SAS exome AF: 0.218

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.0995

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.162 AC: 24669 AN: 151820 Hom.: 2326 Cov.: 32 AF XY: 0.166 AC XY: 12310 AN XY: 74202

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.296

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.144

Alfa AF: 0.120 Hom.: 2747

Bravo AF: 0.173

TwinsUK AF: 0.0955 AC: 354

ALSPAC AF: 0.102 AC: 392

ESP6500AA AF: 0.227 AC: 998

ESP6500EA AF: 0.107 AC: 920

ExAC AF: 0.163 AC: 19776

Asia WGS AF: 0.218 AC: 752 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	This variant is associated with the following publications: (PMID: 23413192, 25075649, 17318641, 32202057) -

KLKB1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	14
DANN	Benign	0.81
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.041	N
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.28
Sift	Benign	0.50	T
Sift4G	Benign	0.45	T
Vest4		0.015
MPC		0.13
ClinPred		0.0011	T
GERP RS		2.1
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.34		Position offset: 46

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4253325; hg19: chr4-187178473; COSMIC: COSV52993991;