rs198977

Positions:

chr19-50878521-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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 Benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.30 ( 7272 hom., cov: 32)

Exomes 𝑓: 0.24 ( 44384 hom. )

Consequence

KLK2
NM_005551.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter P:1B:1

Conservation

PhyloP100: -7.28

Variant links:

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]

KLK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.9420853E-4).

BP6

Variant 19-50878521-C-T is Benign according to our data. Variant chr19-50878521-C-T is described in ClinVar as [Benign]. Clinvar id is 2573115.Status of the report is criteria_provided_single_submitter, 1 stars.

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	Protein	UniProt
KLK2	NM_005551.5 link	c.748C>T	p.Arg250Trp	missense_variant	5/5	ENST00000325321.8	NP_005542.1	P20151-1A0A024R4J4B4DU77

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK2	ENST00000325321.8 link	c.748C>T	p.Arg250Trp	missense_variant	5/5	1	NM_005551.5	ENSP00000313581.2		P20151-1

Frequencies

GnomAD3 genomes

AF:

0.297

AC:

45087

AN:

151848

Hom.:

7255

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.240

AC XY:

174451

AN XY:

727032

show subpopulations

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.:

AF XY:

0.295

AC XY:

21910

AN XY:

74264

show subpopulations

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: Benign

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Acute myeloid leukemia

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	research	Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University	-	- -
Benign, criteria provided, single submitter	research	Eleanor M. Freitas Health Laboratory	Jul 22, 2023	The genetic Variant 'Arg250Trp' within the KLK2 Gene is too frequent to be classified as pathogenic, according to the ACMG guidelines (Richards et al., 2015) this variant meets the following criteria: BA1 (Stand Alone), as it is present in GnomAD exomes with an allele frequency of 0.243, which in turn, is greater than the minimum threshold requirement of >0.05 (with good coverage in gnomAD exomes = 42.9). It also satisfies additional supportive ACMG criteria, such as BP4 (benign-supportive ) with in-silico predictions classifying this variant as 'very strong benign' (meta-score (MetaRNN = 0.000294), which is less than the 0.00692 threshold cut-off. Lastly, an additional "benign supportive" BP6 criterion also been satisfied, due to independent review by Uniprot (VAR_020178) which assessed and classified this variant as 'Likely Benign/Benign' (LB/B). I also refer to a previous study with Meng. et al. (2023) which asserts rs198977 (genotype TT) as being 'associated with an increased risk of AML susceptibility'. However, this study seriously lacks the sufficient and robust sample size required to reach an appropriate conclusion (specifically in respect to the size of the TT genotype sub-group. This in turn, may result in a lower statistical power and yield unreliable estimates regarding the disease-association in question. Moreover there is no mention of specific population demographics used in the study, and this further raises questions about the population diversity recruited in this study. Notwithstanding, the current lack of in-vitro & in-vivo studies to support their results. This means results may suffer a serious lack of reproducibility relating to proving the variant-disease association relating to these results, let alone the specific genotype relating to the variant and the disease. In conclusion the high allele frequency of 0.243 effectively disqualifies this variant from being classified as pathogenic, in accordance with ACMG guidelines and current evidence available (at the time of this variant classification). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.51

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

LIST_S2

Benign

0.039

T;T

MetaRNN

Benign

0.00029

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Benign

0.22

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over