19-50827150-A-G

Variant names:

• chr19-50827150-A-G
• rs779144247
• NM_017509.4:c.209T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017509.4(KLK15):​c.209T>C​(p.Val70Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,586,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: KLK15 NM_017509.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK15	NM_017509.4	c.209T>C	p.Val70Ala	missense_variant	Exon 4 of 6	ENST00000598239.6	NP_059979.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK15	ENST00000598239.6	c.209T>C	p.Val70Ala	missense_variant	Exon 4 of 6	1	NM_017509.4	ENSP00000469315.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152026 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000762 AC: 17 AN: 223056 Hom.: 0 AF XY: 0.0000904 AC XY: 11 AN XY: 121692

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000929

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.0000365

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000321 AC: 46 AN: 1434364 Hom.: 0 Cov.: 31 AF XY: 0.0000309 AC XY: 22 AN XY: 712490

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00112

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000596

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000725

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152026 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74234

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000661 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.209T>C (p.V70A) alteration is located in exon 3 (coding exon 3) of the KLK15 gene. This alteration results from a T to C substitution at nucleotide position 209, causing the valine (V) at amino acid position 70 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	.;D;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.63	T;T;T;T
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.3	.;L;.;.
PrimateAI	Benign	0.47	T
REVEL	Uncertain	0.31
Sift4G	Uncertain	0.032	D;D;D;.
Polyphen		0.071	.;B;.;.
Vest4		0.22
MutPred		0.86		.;Loss of stability (P = 0.0053);.;.;
MVP		0.88
MPC		0.51
ClinPred		0.059	T
GERP RS		-2.8
Varity_R		0.22
gMVP		0.78

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: rs779144247; hg19: chr19-51330406;