NM_017509.4:c.469C>T

Variant names:

• chr19-50826890-G-A
• rs762030515
• NM_017509.4:c.469C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017509.4(KLK15):​c.469C>T​(p.Pro157Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000256 in 1,561,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P157R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KLK15 NM_017509.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0620
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0629046).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK15	NM_017509.4	MANE Select	c.469C>T	p.Pro157Ser	missense	Exon 4 of 6	NP_059979.2
	KLK15	NM_001277081.2		c.466C>T	p.Pro156Ser	missense	Exon 4 of 6	NP_001264010.1	Q9H2R5-5
	KLK15	NM_001277082.2		c.466C>T	p.Pro156Ser	missense	Exon 4 of 5	NP_001264011.1	M0R0D7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK15	ENST00000598239.6	TSL:1 MANE Select	c.469C>T	p.Pro157Ser	missense	Exon 4 of 6	ENSP00000469315.1	Q9H2R5-1
	KLK15	ENST00000596931.5	TSL:1	c.466C>T	p.Pro156Ser	missense	Exon 3 of 4	ENSP00000471164.1	M0R0D7
	KLK15	ENST00000601680.1	TSL:1	n.469C>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000475 AC: 1 AN: 210632 AF XY: 0.00000891

Gnomad AFR exome AF: 0.0000635

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1409722 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 694942

African (AFR) AF: 0.00 AC: 0 AN: 32254

American (AMR) AF: 0.00 AC: 0 AN: 39262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22566

East Asian (EAS) AF: 0.00 AC: 0 AN: 39218

South Asian (SAS) AF: 0.00 AC: 0 AN: 77574

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084656

Other (OTH) AF: 0.0000172 AC: 1 AN: 58090

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74368

African (AFR) AF: 0.0000724 AC: 3 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	10
DANN	Benign	0.65
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.35	N
PhyloP100		0.062
PrimateAI	Benign	0.24	T
REVEL	Benign	0.21
Sift4G	Uncertain	0.056	T
Polyphen		0.0020	B
Vest4		0.15
MutPred		0.29		Gain of phosphorylation at P157 (P = 0.0388)
MVP		0.71
MPC		0.41
ClinPred		0.026	T
GERP RS		-2.1
Varity_R		0.050
gMVP		0.67
Mutation Taster		=98/2	polymorphism

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: rs762030515; hg19: chr19-51330146;