19-50878521-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The NM_005551.5(KLK2):c.748C>T(p.Arg250Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,613,356 control chromosomes in the GnomAD database, including 51,656 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.30 (7272 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44384 hom.)
• Consequence: KLK2 NM_005551.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -7.28

Genes affected

KLK2 (HGNC:6363): (kallikrein related peptidase 2) This gene encodes a member of the grandular kallikrein protein family. Kallikreins are a subgroup of serine proteases that are clustered on chromosome 19. Members of this family are involved in a diverse array of biological functions. The protein encoded by this gene is a highly active trypsin-like serine protease that selectively cleaves at arginine residues. This protein is primarily expressed in prostatic tissue and is responsible for cleaving pro-prostate-specific antigen into its enzymatically active form. This gene is highly expressed in prostate tumor cells and may be a prognostic maker for prostate cancer risk. Alternate splicing results in both coding and non-coding transcript variants. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP5: Variant 19-50878521-C-T is Pathogenic according to our data. Variant chr19-50878521-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2573115.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=2.9420853E-4).. Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK2	NM_005551.5	c.748C>T	p.Arg250Trp	missense_variant	5/5	ENST00000325321.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK2	ENST00000325321.8	c.748C>T	p.Arg250Trp	missense_variant	5/5	1	NM_005551.5	P1

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45087 AN: 151848 Hom.: 7255 Cov.: 32

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.306

GnomAD3 exomes AF: 0.244 AC: 61217 AN: 251292 Hom.: 8116 AF XY: 0.239 AC XY: 32510 AN XY: 135812

Gnomad AFR exome AF: 0.429

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.258

Gnomad EAS exome AF: 0.188

Gnomad SAS exome AF: 0.153

Gnomad FIN exome AF: 0.323

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.243 AC: 354835 AN: 1461390 Hom.: 44384 Cov.: 33 AF XY: 0.240 AC XY: 174451 AN XY: 727032

Gnomad4 AFR exome AF: 0.422

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.260

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.153

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.242

Gnomad4 OTH exome AF: 0.256

GnomAD4 genome AF: 0.297 AC: 45135 AN: 151966 Hom.: 7272 Cov.: 32 AF XY: 0.295 AC XY: 21910 AN XY: 74264

Gnomad4 AFR AF: 0.424

Gnomad4 AMR AF: 0.249

Gnomad4 ASJ AF: 0.259

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.314

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.307

Alfa AF: 0.255 Hom.: 6880

Bravo AF: 0.301

TwinsUK AF: 0.231 AC: 856

ALSPAC AF: 0.228 AC: 880

ESP6500AA AF: 0.426 AC: 1879

ESP6500EA AF: 0.247 AC: 2124

ExAC AF: 0.247 AC: 29972

Asia WGS AF: 0.213 AC: 745 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acute myeloid leukemia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	1.1
Dann	Benign	0.63
DEOGEN2	Benign	0.35	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.039	T;T
MetaRNN	Benign	0.00029	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.16	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.23	B;.
Vest4		0.061
MPC		0.053
ClinPred		0.012	T
GERP RS		-7.1
Varity_R		0.24
gMVP		0.70

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: rs198977; hg19: chr19-51381777; COSMIC: COSV57568931; COSMIC: COSV57568931;