rs2304595

chr4-186251126-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 0.269

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.

• 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 id is 1274237.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLKB1	NM_000892.5	c.759-93G>A		intron_variant		ENST00000264690.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLKB1	ENST00000264690.11	c.759-93G>A		intron_variant		1	NM_000892.5	P1
KLKB1	ENST00000511406.5	n.820-93G>A		intron_variant, non_coding_transcript_variant		1
KLKB1	ENST00000513864.2	c.645-93G>A		intron_variant		2
KLKB1	ENST00000467271.1	n.95G>A		non_coding_transcript_exon_variant	1/4	2

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

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.353

Gnomad4 ASJ exome AF: 0.294

Gnomad4 EAS exome AF: 0.347

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.453

Gnomad4 NFE exome AF: 0.407

Gnomad4 OTH exome AF: 0.373

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

Gnomad4 AFR AF: 0.268

Gnomad4 AMR AF: 0.364

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.385

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.457

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.381

Alfa AF: 0.386 Hom.: 2742

Bravo AF: 0.351

Asia WGS AF: 0.284 AC: 988 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	4.7
Dann	Benign	0.53

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: rs2304595; hg19: chr4-187172280;