rs4253325

Variant names:

• chr4-186257319-G-A
• rs4253325
• NM_000892.5:c.1679G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000892.5(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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2326 hom., cov: 32)
  • Exomes 𝑓: 0.12 (13264 hom.)
• Consequence: KLKB1 NM_000892.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.59
• Publications: 29 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ENSG00000290316 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 4-186257319-G-A is Benign according to our data. Variant chr4-186257319-G-A is described in ClinVar as Benign. ClinVar VariationId is 1297284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000892.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLKB1	NM_000892.5	MANE Select	c.1679G>A	p.Arg560Gln	missense	Exon 14 of 15	NP_000883.2	P03952
	KLKB1	NM_001318396.2		c.1073G>A	p.Arg358Gln	missense	Exon 14 of 15	NP_001305325.1
	KLKB1	NM_001440521.1		c.1586-702G>A		intron	N/A	NP_001427450.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLKB1	ENST00000264690.11	TSL:1 MANE Select	c.1679G>A	p.Arg560Gln	missense	Exon 14 of 15	ENSP00000264690.6	P03952
	ENSG00000290316	ENST00000511608.5	TSL:5	c.1820G>A	p.Arg607Gln	missense	Exon 14 of 15	ENSP00000426629.1	H0YAC1
	KLKB1	ENST00000511406.5	TSL:1	n.1740G>A		non_coding_transcript_exon	Exon 14 of 15

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

GnomAD2 exomes AF: 0.165 AC: 41154 AN: 249108 AF XY: 0.161

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 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

African (AFR) AF: 0.239 AC: 7937 AN: 33198

American (AMR) AF: 0.248 AC: 10974 AN: 44186

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3588 AN: 25866

East Asian (EAS) AF: 0.294 AC: 11495 AN: 39154

South Asian (SAS) AF: 0.218 AC: 18360 AN: 84314

European-Finnish (FIN) AF: 0.124 AC: 6546 AN: 52800

Middle Eastern (MID) AF: 0.164 AC: 935 AN: 5706

European-Non Finnish (NFE) AF: 0.0995 AC: 109906 AN: 1105026

Other (OTH) AF: 0.141 AC: 8422 AN: 59848

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

African (AFR) AF: 0.234 AC: 9698 AN: 41380

American (AMR) AF: 0.198 AC: 3015 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 524 AN: 3472

East Asian (EAS) AF: 0.296 AC: 1522 AN: 5150

South Asian (SAS) AF: 0.227 AC: 1097 AN: 4822

European-Finnish (FIN) AF: 0.130 AC: 1363 AN: 10484

Middle Eastern (MID) AF: 0.169 AC: 49 AN: 290

European-Non Finnish (NFE) AF: 0.102 AC: 6938 AN: 67982

Other (OTH) AF: 0.144 AC: 304 AN: 2108

Alfa AF: 0.126 Hom.: 6462

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	KLKB1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.6
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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