rs2304595

Variant names:

• chr4-186251126-G-A
• rs2304595
• NM_000892.5:c.759-93G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000892.5(KLKB1):​c.759-93G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 786,446 control chromosomes in the GnomAD database, including 56,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10199 hom., cov: 32)
  • Exomes 𝑓: 0.37 (46225 hom.)
• Consequence: KLKB1 NM_000892.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.269
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-186251126-G-A is Benign according to our data. Variant chr4-186251126-G-A is described in ClinVar as Benign. ClinVar VariationId is 1274237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.405 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLKB1	NM_000892.5	MANE Select	c.759-93G>A		intron	N/A	NP_000883.2
	KLKB1	NM_001440521.1		c.759-93G>A		intron	N/A	NP_001427450.1
	KLKB1	NM_001318394.2		c.645-93G>A		intron	N/A	NP_001305323.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLKB1	ENST00000264690.11	TSL:1 MANE Select	c.759-93G>A		intron	N/A	ENSP00000264690.6
	ENSG00000290316	ENST00000511608.5	TSL:5	c.900-93G>A		intron	N/A	ENSP00000426629.1
	KLKB1	ENST00000511406.5	TSL:1	n.820-93G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.358 AC: 54318 AN: 151840 Hom.: 10192 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.378

GnomAD4 exome AF: 0.372 AC: 235959 AN: 634488 Hom.: 46225 Cov.: 8 AF XY: 0.362 AC XY: 123162 AN XY: 340636

African (AFR) AF: 0.268 AC: 4188 AN: 15620

American (AMR) AF: 0.353 AC: 10731 AN: 30432

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 5705 AN: 19418

East Asian (EAS) AF: 0.347 AC: 11886 AN: 34224

South Asian (SAS) AF: 0.160 AC: 9734 AN: 60712

European-Finnish (FIN) AF: 0.453 AC: 21860 AN: 48276

Middle Eastern (MID) AF: 0.284 AC: 858 AN: 3018

European-Non Finnish (NFE) AF: 0.407 AC: 158837 AN: 390174

Other (OTH) AF: 0.373 AC: 12160 AN: 32614

GnomAD4 genome AF: 0.358 AC: 54349 AN: 151958 Hom.: 10199 Cov.: 32 AF XY: 0.356 AC XY: 26420 AN XY: 74272

African (AFR) AF: 0.268 AC: 11120 AN: 41438

American (AMR) AF: 0.364 AC: 5561 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1018 AN: 3472

East Asian (EAS) AF: 0.385 AC: 1991 AN: 5174

South Asian (SAS) AF: 0.160 AC: 771 AN: 4818

European-Finnish (FIN) AF: 0.457 AC: 4805 AN: 10520

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27783 AN: 67952

Other (OTH) AF: 0.381 AC: 803 AN: 2110

Alfa AF: 0.383 Hom.: 2772

Bravo AF: 0.351

Asia WGS AF: 0.284 AC: 988 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.7
DANN	Benign	0.53
PhyloP100		0.27
Mutation Taster		=100/0	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: rs2304595; hg19: chr4-187172280;