chr4-186232357-T-C

Variant names:

• chr4-186232357-T-C
• rs4253243
• NM_000892.5:c.221+68T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0120
• Publications: 7 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), ClinGen, Orphanet

ENSG00000290316 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 1280555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000892.5. 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
	KLKB1	NM_000892.5	MANE Select	c.221+68T>C		intron	N/A	NP_000883.2	P03952
	KLKB1	NM_001440521.1		c.221+68T>C		intron	N/A	NP_001427450.1
	KLKB1	NM_001318394.2		c.107+68T>C		intron	N/A	NP_001305323.1	E9PBC5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLKB1	ENST00000264690.11	TSL:1 MANE Select	c.221+68T>C		intron	N/A	ENSP00000264690.6	P03952
	ENSG00000290316	ENST00000511608.5	TSL:5	c.362+68T>C		intron	N/A	ENSP00000426629.1	H0YAC1
	KLKB1	ENST00000511406.5	TSL:1	n.251+68T>C		intron	N/A

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

African (AFR) AF: 0.0128 AC: 385 AN: 30058

American (AMR) AF: 0.0291 AC: 1293 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3256 AN: 24968

East Asian (EAS) AF: 0.00597 AC: 232 AN: 38890

South Asian (SAS) AF: 0.200 AC: 16440 AN: 82210

European-Finnish (FIN) AF: 0.0556 AC: 2955 AN: 53124

Middle Eastern (MID) AF: 0.110 AC: 595 AN: 5430

European-Non Finnish (NFE) AF: 0.0792 AC: 75769 AN: 956326

Other (OTH) AF: 0.0770 AC: 4215 AN: 54724

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

African (AFR) AF: 0.0150 AC: 623 AN: 41554

American (AMR) AF: 0.0391 AC: 598 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 454 AN: 3470

East Asian (EAS) AF: 0.00810 AC: 42 AN: 5184

South Asian (SAS) AF: 0.191 AC: 920 AN: 4822

European-Finnish (FIN) AF: 0.0508 AC: 538 AN: 10600

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0827 AC: 5627 AN: 68010

Other (OTH) AF: 0.0705 AC: 149 AN: 2112

Alfa AF: 0.0712 Hom.: 379

Bravo AF: 0.0520

Asia WGS AF: 0.0890 AC: 309 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.37
PhyloP100		-0.012
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4253243; hg19: chr4-187153511;