NM_000892.5:c.-1-116T>C

Variant names:

• chr4-186228079-T-C
• rs4253241
• NM_000892.5:c.-1-116T>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.-1-116T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 703,218 control chromosomes in the GnomAD database, including 5,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (909 hom., cov: 32)
  • Exomes 𝑓: 0.12 (4509 hom.)
• Consequence: KLKB1 NM_000892.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.955
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-186228079-T-C is Benign according to our data. Variant chr4-186228079-T-C is described in ClinVar as Benign. ClinVar VariationId is 1275028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.18 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.-1-116T>C		intron	N/A	NP_000883.2	P03952
	KLKB1	NM_001440521.1		c.-1-116T>C		intron	N/A	NP_001427450.1
	KLKB1	NM_001318394.2		c.-184-166T>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.-1-116T>C		intron	N/A	ENSP00000264690.6	P03952
	ENSG00000290316	ENST00000511608.5	TSL:5	c.200-4048T>C		intron	N/A	ENSP00000426629.1	H0YAC1
	KLKB1	ENST00000511406.5	TSL:1	n.30-116T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15859 AN: 152154 Hom.: 910 Cov.: 32

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0773

Gnomad EAS AF: 0.0609

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.0968

GnomAD4 exome AF: 0.122 AC: 67445 AN: 550946 Hom.: 4509 AF XY: 0.126 AC XY: 37504 AN XY: 296650

African (AFR) AF: 0.0605 AC: 906 AN: 14968

American (AMR) AF: 0.0956 AC: 2993 AN: 31320

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 1595 AN: 18810

East Asian (EAS) AF: 0.0656 AC: 2052 AN: 31268

South Asian (SAS) AF: 0.183 AC: 10792 AN: 58986

European-Finnish (FIN) AF: 0.146 AC: 5918 AN: 40402

Middle Eastern (MID) AF: 0.113 AC: 321 AN: 2850

European-Non Finnish (NFE) AF: 0.123 AC: 39630 AN: 322628

Other (OTH) AF: 0.109 AC: 3238 AN: 29714

GnomAD4 genome AF: 0.104 AC: 15859 AN: 152272 Hom.: 909 Cov.: 32 AF XY: 0.108 AC XY: 8060 AN XY: 74454

African (AFR) AF: 0.0596 AC: 2478 AN: 41586

American (AMR) AF: 0.109 AC: 1661 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0773 AC: 268 AN: 3468

East Asian (EAS) AF: 0.0609 AC: 316 AN: 5192

South Asian (SAS) AF: 0.190 AC: 917 AN: 4820

European-Finnish (FIN) AF: 0.145 AC: 1533 AN: 10586

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8299 AN: 68016

Other (OTH) AF: 0.0963 AC: 203 AN: 2108

Alfa AF: 0.111 Hom.: 126

Bravo AF: 0.0964

Asia WGS AF: 0.130 AC: 449 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	-0.81
CADD	Benign	5.2
DANN	Benign	0.45
PhyloP100		0.95
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: rs4253241; hg19: chr4-187149233;