NM_017509.4:c.238C>T

Variant names:

• chr19-50827121-G-A
• rs374766999
• NM_017509.4:c.238C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_017509.4(KLK15):​c.238C>T​(p.Arg80Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000225 in 1,601,176 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign 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. R80S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (2 hom.)
• Consequence: KLK15 NM_017509.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00300
• Publications: 2 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20732492).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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.238C>T	p.Arg80Cys	missense	Exon 4 of 6	NP_059979.2
	KLK15	NM_001277081.2		c.235C>T	p.Arg79Cys	missense	Exon 4 of 6	NP_001264010.1	Q9H2R5-5
	KLK15	NM_001277082.2		c.235C>T	p.Arg79Cys	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.238C>T	p.Arg80Cys	missense	Exon 4 of 6	ENSP00000469315.1	Q9H2R5-1
	KLK15	ENST00000596931.5	TSL:1	c.235C>T	p.Arg79Cys	missense	Exon 3 of 4	ENSP00000471164.1	M0R0D7
	KLK15	ENST00000601680.1	TSL:1	n.238C>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000503 AC: 12 AN: 238730 AF XY: 0.0000384

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000242 AC: 35 AN: 1448826 Hom.: 2 Cov.: 31 AF XY: 0.0000222 AC XY: 16 AN XY: 721092

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.000338 AC: 29 AN: 85926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110606

Other (OTH) AF: 0.0000498 AC: 3 AN: 60250

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74498

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000157 Hom.: 1

Bravo AF: 0.0000113

ExAC AF: 0.0000495 AC: 6

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.0030
PrimateAI	Benign	0.34	T
REVEL	Uncertain	0.30
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.42
MutPred		0.39		Loss of MoRF binding (P = 0.0064)
MVP		0.91
MPC		1.3
ClinPred		0.29	T
GERP RS		2.4
Varity_R		0.37
gMVP		0.62
Mutation Taster		=96/4	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: rs374766999; hg19: chr19-51330377;