4-186228079-T-C

Position:

• chr4-186228079-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLKB1	NM_000892.5	c.-1-116T>C		intron_variant		ENST00000264690.11	NP_000883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLKB1	ENST00000264690.11	c.-1-116T>C		intron_variant		1	NM_000892.5	ENSP00000264690	P1

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

Gnomad4 AFR exome AF: 0.0605

Gnomad4 AMR exome AF: 0.0956

Gnomad4 ASJ exome AF: 0.0848

Gnomad4 EAS exome AF: 0.0656

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.109

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

Gnomad4 AFR AF: 0.0596

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0773

Gnomad4 EAS AF: 0.0609

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.0963

Alfa AF: 0.113 Hom.: 126

Bravo AF: 0.0964

Asia WGS AF: 0.130 AC: 449 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.2
DANN	Benign	0.45

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: rs4253241; hg19: chr4-187149233;