rs1259601559

Variant names:

• chr4-186232145-A-C
• rs1259601559
• NM_000892.5:c.77A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-186232145-A-C
• chr4-186232145-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001318394.2(KLKB1):​c.-38A>C variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000685 in 1,460,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLKB1 NM_001318394.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.19
• Publications: 0 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), Orphanet, ClinGen

ENSG00000290316 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318394.2. 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.77A>C	p.Tyr26Ser	missense	Exon 3 of 15	NP_000883.2	P03952
	KLKB1	NM_001318394.2		c.-38A>C		5_prime_UTR_premature_start_codon_gain	Exon 4 of 15	NP_001305323.1	E9PBC5
	KLKB1	NM_001318396.2		c.-561A>C		5_prime_UTR_premature_start_codon_gain	Exon 3 of 15	NP_001305325.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLKB1	ENST00000264690.11	TSL:1 MANE Select	c.77A>C	p.Tyr26Ser	missense	Exon 3 of 15	ENSP00000264690.6	P03952
	ENSG00000290316	ENST00000511608.5	TSL:5	c.218A>C	p.Tyr73Ser	missense	Exon 3 of 15	ENSP00000426629.1	H0YAC1
	KLKB1	ENST00000511406.5	TSL:1	n.107A>C		non_coding_transcript_exon	Exon 3 of 15

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460536 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726370

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111142

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.20	D
PhyloP100		4.2
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.025	D
Vest4		0.77
MutPred		0.82		Loss of helix (P = 0.0626)
MVP		0.92
MPC		0.61
ClinPred		0.99	D
GERP RS		5.3
gMVP		0.97
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1259601559; hg19: chr4-187153299;