19-50826873-C-T

Variant names:

• chr19-50826873-C-T
• rs3212852
• NM_017509.4:c.481+5G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_017509.4(KLK15):​c.481+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,558,560 control chromosomes in the GnomAD database, including 392 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (44 hom., cov: 32)
  • Exomes 𝑓: 0.019 (348 hom.)
• Consequence: KLK15 NM_017509.4 splice_region, intron
• Scores: Splicing: ADA: 0.9547
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.277
• Publications: 8 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0169 (2571/152332) while in subpopulation NFE AF = 0.0232 (1581/68016). AF 95% confidence interval is 0.0223. There are 44 homozygotes in GnomAd4. There are 1346 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 44 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.481+5G>A		splice_region intron	N/A	NP_059979.2
	KLK15	NM_001277081.2		c.478+5G>A		splice_region intron	N/A	NP_001264010.1	Q9H2R5-5
	KLK15	NM_001277082.2		c.478+5G>A		splice_region intron	N/A	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.481+5G>A		splice_region intron	N/A	ENSP00000469315.1	Q9H2R5-1
	KLK15	ENST00000596931.5	TSL:1	c.478+5G>A		splice_region intron	N/A	ENSP00000471164.1	M0R0D7
	KLK15	ENST00000601680.1	TSL:1	n.486G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2573 AN: 152214 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0546

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0179 AC: 3738 AN: 208336 AF XY: 0.0183

Gnomad AFR exome AF: 0.00367

Gnomad AMR exome AF: 0.00570

Gnomad ASJ exome AF: 0.0231

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.0195 AC: 27386 AN: 1406228 Hom.: 348 Cov.: 31 AF XY: 0.0192 AC XY: 13291 AN XY: 692836

African (AFR) AF: 0.00274 AC: 88 AN: 32122

American (AMR) AF: 0.00605 AC: 234 AN: 38664

Ashkenazi Jewish (ASJ) AF: 0.0224 AC: 496 AN: 22186

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39236

South Asian (SAS) AF: 0.00478 AC: 366 AN: 76582

European-Finnish (FIN) AF: 0.0491 AC: 2485 AN: 50646

Middle Eastern (MID) AF: 0.00471 AC: 26 AN: 5522

European-Non Finnish (NFE) AF: 0.0210 AC: 22708 AN: 1083354

Other (OTH) AF: 0.0170 AC: 982 AN: 57916

GnomAD4 genome AF: 0.0169 AC: 2571 AN: 152332 Hom.: 44 Cov.: 32 AF XY: 0.0181 AC XY: 1346 AN XY: 74498

African (AFR) AF: 0.00327 AC: 136 AN: 41588

American (AMR) AF: 0.00889 AC: 136 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 83 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4832

European-Finnish (FIN) AF: 0.0546 AC: 580 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0232 AC: 1581 AN: 68016

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.0177 Hom.: 44

Bravo AF: 0.0122

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	18
DANN	Benign	0.86
PhyloP100		0.28
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.59		Position offset: 5

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

Other links and lift over

dbSNP: rs3212852; hg19: chr19-51330129;