rs4253238

Variant names:

• chr4-186227233-C-T
• rs4253238
• ENST00000511608.5:c.200-4894C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000511608.5(ENSG00000290316):​c.200-4894C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 152,012 control chromosomes in the GnomAD database, including 27,161 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.59 (27161 hom., cov: 32)
• Consequence: ENSG00000290316 ENST00000511608.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.778
• Publications: 29 publications found

Genes affected

ENSG00000290316 (HGNC:):

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLKB1	XM_017008181.2	c.-1-962C>T		intron_variant	Intron 1 of 14		XP_016863670.1
KLKB1	XM_047415661.1	c.-1-962C>T		intron_variant	Intron 3 of 16		XP_047271617.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000290316	ENST00000511608.5	c.200-4894C>T		intron_variant	Intron 2 of 14	5		ENSP00000426629.1
KLKB1	ENST00000428196.5	c.-149-207C>T		intron_variant	Intron 1 of 5	3		ENSP00000412366.1

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89291 AN: 151894 Hom.: 27110 Cov.: 32

Gnomad AFR AF: 0.741

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.584

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: 0.568

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

GnomAD4 genome AF: 0.588 AC: 89396 AN: 152012 Hom.: 27161 Cov.: 32 AF XY: 0.587 AC XY: 43613 AN XY: 74292

African (AFR) AF: 0.742 AC: 30750 AN: 41470

American (AMR) AF: 0.585 AC: 8926 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1539 AN: 3470

East Asian (EAS) AF: 0.680 AC: 3512 AN: 5166

South Asian (SAS) AF: 0.395 AC: 1902 AN: 4810

European-Finnish (FIN) AF: 0.582 AC: 6135 AN: 10544

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

European-Non Finnish (NFE) AF: 0.511 AC: 34718 AN: 67966

Other (OTH) AF: 0.569 AC: 1202 AN: 2112

Alfa AF: 0.534 Hom.: 70362

Bravo AF: 0.600

Asia WGS AF: 0.531 AC: 1849 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.62
DANN	Benign	0.44
PhyloP100		-0.78
PromoterAI		-0.0067	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4253238; hg19: chr4-187148387;