19-50827150-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.209T>C	p.Val70Ala	missense	Exon 4 of 6	NP_059979.2
	KLK15	NM_001277081.2		c.206T>C	p.Val69Ala	missense	Exon 4 of 6	NP_001264010.1	Q9H2R5-5
	KLK15	NM_001277082.2		c.206T>C	p.Val69Ala	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.209T>C	p.Val70Ala	missense	Exon 4 of 6	ENSP00000469315.1	Q9H2R5-1
	KLK15	ENST00000596931.5	TSL:1	c.206T>C	p.Val69Ala	missense	Exon 3 of 4	ENSP00000471164.1	M0R0D7
	KLK15	ENST00000601680.1	TSL:1	n.209T>C		non_coding_transcript_exon	Exon 3 of 4

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

GnomAD2 exomes AF: 0.0000762 AC: 17 AN: 223056 AF XY: 0.0000904

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 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

African (AFR) AF: 0.0000300 AC: 1 AN: 33308

American (AMR) AF: 0.00 AC: 0 AN: 43936

Ashkenazi Jewish (ASJ) AF: 0.00112 AC: 28 AN: 25008

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39540

South Asian (SAS) AF: 0.0000596 AC: 5 AN: 83882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39978

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5584

European-Non Finnish (NFE) AF: 0.00000725 AC: 8 AN: 1103398

Other (OTH) AF: 0.0000335 AC: 2 AN: 59730

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

African (AFR) AF: 0.000121 AC: 5 AN: 41372

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000661 AC: 8

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	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
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.3	L
PhyloP100		2.5
PrimateAI	Benign	0.47	T
REVEL	Uncertain	0.31
Sift4G	Uncertain	0.032	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
Mutation Taster		=69/31	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: rs779144247; hg19: chr19-51330406;