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: Orphanet, ClinGen, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000511608.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000290316	ENST00000511608.5	TSL:5	c.200-4894C>T		intron	N/A	ENSP00000426629.1	H0YAC1
	KLKB1	ENST00000860322.1		c.-963C>T		5_prime_UTR	Exon 1 of 14	ENSP00000530381.1
	KLKB1	ENST00000860321.1		c.-963C>T		5_prime_UTR	Exon 1 of 14	ENSP00000530380.1

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 v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4253238;

hg19: chr4-187148387;