NM_000892.5:c.222-233T>C

Variant names:

• chr4-186233719-T-C
• rs2304596
• NM_000892.5:c.222-233T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000892.5(KLKB1):​c.222-233T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,260 control chromosomes in the GnomAD database, including 1,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.13 (1512 hom., cov: 33)
• Consequence: KLKB1 NM_000892.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.858
• Publications: 7 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), ClinGen, Orphanet

ENSG00000290316 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-186233719-T-C is Benign according to our data. Variant chr4-186233719-T-C is described in ClinVar as Benign. ClinVar VariationId is 1275106.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.17 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.222-233T>C		intron	N/A	NP_000883.2	P03952
	KLKB1	NM_001440521.1		c.222-233T>C		intron	N/A	NP_001427450.1
	KLKB1	NM_001318394.2		c.108-233T>C		intron	N/A	NP_001305323.1	E9PBC5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLKB1	ENST00000264690.11	TSL:1 MANE Select	c.222-233T>C		intron	N/A	ENSP00000264690.6	P03952
	ENSG00000290316	ENST00000511608.5	TSL:5	c.363-233T>C		intron	N/A	ENSP00000426629.1	H0YAC1
	KLKB1	ENST00000511406.5	TSL:1	n.252-233T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19076 AN: 152142 Hom.: 1510 Cov.: 33

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.162

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.125 AC: 19075 AN: 152260 Hom.: 1512 Cov.: 33 AF XY: 0.122 AC XY: 9120 AN XY: 74450

African (AFR) AF: 0.0331 AC: 1375 AN: 41574

American (AMR) AF: 0.134 AC: 2043 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 786 AN: 3470

East Asian (EAS) AF: 0.175 AC: 907 AN: 5174

South Asian (SAS) AF: 0.100 AC: 484 AN: 4830

European-Finnish (FIN) AF: 0.111 AC: 1180 AN: 10612

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11724 AN: 67994

Other (OTH) AF: 0.162 AC: 343 AN: 2116

Alfa AF: 0.139 Hom.: 263

Bravo AF: 0.125

Asia WGS AF: 0.147 AC: 513 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.9
DANN	Benign	0.39
PhyloP100		0.86
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: rs2304596; hg19: chr4-187154873;