Genetic Variant NM_017509.4:c.209T>G (chr19-50827150-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_017509.4(KLK15):c.209T>G(p.Val70Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,434,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V70A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KLK15
NM_017509.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.49

Publications

1 publications found

Variant links:

Genes affected

KLK15 (HGNC:20453): (kallikrein related peptidase 15) Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. In prostate cancer, this gene has increased expression, which indicates its possible use as a diagnostic or prognostic marker for prostate cancer. The gene contains multiple polyadenylation sites and alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

KLK15 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017509.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLK15	NM_017509.4	MANE Select	c.209T>G	p.Val70Gly	missense	Exon 4 of 6	NP_059979.2
KLK15	NM_001277081.2		c.206T>G	p.Val69Gly	missense	Exon 4 of 6	NP_001264010.1	Q9H2R5-5
KLK15	NM_001277082.2		c.206T>G	p.Val69Gly	missense	Exon 4 of 5	NP_001264011.1	M0R0D7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLK15	ENST00000598239.6	TSL:1 MANE Select	c.209T>G	p.Val70Gly	missense	Exon 4 of 6	ENSP00000469315.1	Q9H2R5-1
KLK15	ENST00000596931.5	TSL:1	c.206T>G	p.Val69Gly	missense	Exon 3 of 4	ENSP00000471164.1	M0R0D7
KLK15	ENST00000601680.1	TSL:1	n.209T>G		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000448

AC:

AN:

223056

AF XY:

0.00000822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000975

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1434362

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712490

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33308

American (AMR)

AF:

0.00

AC:

AN:

43936

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25008

East Asian (EAS)

AF:

0.00

AC:

AN:

39540

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5584

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103398

Other (OTH)

AF:

0.00

AC:

AN:

59730

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000826

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Benign

0.058

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.53

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

3.1

PhyloP100

2.5

PrimateAI

Benign

0.40

REVEL

Pathogenic

0.68

Sift4G

Pathogenic

0.0

Polyphen

0.98

Vest4

0.39

MutPred

0.87

Loss of stability (P = 9e-04)

MVP

0.92

MPC

0.61

ClinPred

0.77

GERP RS

-2.8

Varity_R

0.75

gMVP

0.94

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over