4-186232357-T-C

Position:

• chr4-186232357-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000892.5(KLKB1):​c.221+68T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0791 in 1,442,398 control chromosomes in the GnomAD database, including 5,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.059 (383 hom., cov: 33)
  • Exomes 𝑓: 0.081 (5526 hom.)
• Consequence: KLKB1 NM_000892.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0120

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-186232357-T-C is Benign according to our data. Variant chr4-186232357-T-C is described in ClinVar as [Benign]. Clinvar id is 1280555.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLKB1	NM_000892.5	c.221+68T>C		intron_variant		ENST00000264690.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLKB1	ENST00000264690.11	c.221+68T>C		intron_variant		1	NM_000892.5	P1

Frequencies

GnomAD3 genomes AF: 0.0591 AC: 8990 AN: 152130 Hom.: 383 Cov.: 33

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0392

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.00808

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.0508

Gnomad MID AF: 0.0860

Gnomad NFE AF: 0.0827

Gnomad OTH AF: 0.0708

GnomAD4 exome AF: 0.0815 AC: 105140 AN: 1290150 Hom.: 5526 AF XY: 0.0870 AC XY: 56606 AN XY: 650794

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.0291

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.00597

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.0556

Gnomad4 NFE exome AF: 0.0792

Gnomad4 OTH exome AF: 0.0770

GnomAD4 genome AF: 0.0590 AC: 8986 AN: 152248 Hom.: 383 Cov.: 33 AF XY: 0.0587 AC XY: 4366 AN XY: 74430

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.0391

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.00810

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.0508

Gnomad4 NFE AF: 0.0827

Gnomad4 OTH AF: 0.0705

Alfa AF: 0.0730 Hom.: 313

Bravo AF: 0.0520

Asia WGS AF: 0.0890 AC: 309 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs4253243; hg19: chr4-187153511;