rs1912826

Variant names:

• chr4-186228386-G-A
• rs1912826
• NM_000892.5:c.58+133G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-186228386-G-A
• chr4-186228386-G-C

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.58+133G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 679,390 control chromosomes in the GnomAD database, including 95,899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24245 hom., cov: 31)
  • Exomes 𝑓: 0.52 (71654 hom.)
• Consequence: KLKB1 NM_000892.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.140
• Publications: 26 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=-0.91).
• BP6: Variant 4-186228386-G-A is Benign according to our data. Variant chr4-186228386-G-A is described in ClinVar as [Benign]. Clinvar id is 1263748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLKB1	NM_000892.5	c.58+133G>A		intron_variant	Intron 2 of 14	ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11	c.58+133G>A		intron_variant	Intron 2 of 14	1	NM_000892.5	ENSP00000264690.6
ENSG00000290316	ENST00000511608.5	c.200-3741G>A		intron_variant	Intron 2 of 14	5		ENSP00000426629.1

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85076 AN: 151754 Hom.: 24215 Cov.: 31

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.547

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.554

GnomAD4 exome AF: 0.515 AC: 271689 AN: 527518 Hom.: 71654 AF XY: 0.504 AC XY: 143664 AN XY: 284818

African (AFR) AF: 0.650 AC: 9668 AN: 14884

American (AMR) AF: 0.615 AC: 19481 AN: 31672

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 8131 AN: 18638

East Asian (EAS) AF: 0.639 AC: 20011 AN: 31332

South Asian (SAS) AF: 0.390 AC: 23051 AN: 59126

European-Finnish (FIN) AF: 0.576 AC: 22009 AN: 38210

Middle Eastern (MID) AF: 0.466 AC: 1807 AN: 3876

European-Non Finnish (NFE) AF: 0.506 AC: 152205 AN: 300836

Other (OTH) AF: 0.530 AC: 15326 AN: 28944

GnomAD4 genome AF: 0.561 AC: 85158 AN: 151872 Hom.: 24245 Cov.: 31 AF XY: 0.560 AC XY: 41588 AN XY: 74210

African (AFR) AF: 0.645 AC: 26738 AN: 41424

American (AMR) AF: 0.577 AC: 8797 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1539 AN: 3468

East Asian (EAS) AF: 0.680 AC: 3499 AN: 5144

South Asian (SAS) AF: 0.396 AC: 1904 AN: 4812

European-Finnish (FIN) AF: 0.582 AC: 6124 AN: 10524

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34674 AN: 67926

Other (OTH) AF: 0.555 AC: 1171 AN: 2110

Alfa AF: 0.519 Hom.: 93229

Bravo AF: 0.570

Asia WGS AF: 0.524 AC: 1823 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.51
DANN	Benign	0.44
PhyloP100		-0.14
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: rs1912826; hg19: chr4-187149540; COSMIC: COSV52994575;