rs3212852

Positions:

• chr19-50826873-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000598239.6(KLK15):​c.481+5G>A variant causes a splice donor 5th base, 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.017 (44 hom., cov: 32)
  • Exomes 𝑓: 0.019 (348 hom.)
• Consequence: KLK15 ENST00000598239.6 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9547
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.277

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 Benign. Variant got -12 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK15	NM_017509.4	c.481+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000598239.6	NP_059979.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK15	ENST00000598239.6	c.481+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_017509.4	ENSP00000469315	P4

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

GnomAD3 exomes AF: 0.0179 AC: 3738 AN: 208336 Hom.: 73 AF XY: 0.0183 AC XY: 2021 AN XY: 110520

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 SAS exome AF: 0.00500

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

Gnomad4 AFR exome AF: 0.00274

Gnomad4 AMR exome AF: 0.00605

Gnomad4 ASJ exome AF: 0.0224

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00478

Gnomad4 FIN exome AF: 0.0491

Gnomad4 NFE exome AF: 0.0210

Gnomad4 OTH exome AF: 0.0170

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

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0546

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0185 Hom.: 37

Bravo AF: 0.0122

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	18
DANN	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs3212852; hg19: chr19-51330129;