rs2292186

chr19-50855138-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001648.2(KLK3):c.46+137C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 797,496 control chromosomes in the GnomAD database, including 29,151 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.

• Frequency:
  • Genomes: 𝑓 0.23 (4719 hom., cov: 28)
  • Exomes 𝑓: 0.27 (24432 hom.)
• Consequence: KLK3 NM_001648.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.446

Genes affected

KLK3 (HGNC:6364): (kallikrein related peptidase 3) 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. The gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. It encodes a single-chain glycoprotein, a protease which is synthesized in the epithelial cells of the prostate gland, and is present in seminal plasma. It is thought to function normally in the liquefaction of seminal coagulum, presumably by hydrolysis of the high molecular mass seminal vesicle protein. The serum level of this protein, called PSA in the clinical setting, is useful in the diagnosis and monitoring of prostatic carcinoma. Alternate splicing of this gene generates several transcript variants encoding different isoforms. [provided by RefSeq, Dec 2019]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK3	NM_001648.2	c.46+137C>T		intron_variant		ENST00000326003.7
KLK3	NM_001030047.1	c.46+137C>T		intron_variant
KLK3	NM_001030048.1	c.46+137C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK3	ENST00000326003.7	c.46+137C>T		intron_variant		1	NM_001648.2	P1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34451 AN: 151134 Hom.: 4713 Cov.: 28

Gnomad AFR AF: 0.0878

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.215

GnomAD3 exomes AF: 0.280 AC: 30990 AN: 110526 Hom.: 4727 AF XY: 0.272 AC XY: 15666 AN XY: 57520

Gnomad AFR exome AF: 0.0853

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.355

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.267 AC: 172389 AN: 646246 Hom.: 24432 Cov.: 8 AF XY: 0.262 AC XY: 88860 AN XY: 339646

Gnomad4 AFR exome AF: 0.0858

Gnomad4 AMR exome AF: 0.398

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.347

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.341

Gnomad4 NFE exome AF: 0.269

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.228 AC: 34469 AN: 151250 Hom.: 4719 Cov.: 28 AF XY: 0.230 AC XY: 16960 AN XY: 73808

Gnomad4 AFR AF: 0.0877

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.350

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.344

Gnomad4 NFE AF: 0.269

Gnomad4 OTH AF: 0.222

Alfa AF: 0.246 Hom.: 1288

Bravo AF: 0.222

Asia WGS AF: 0.262 AC: 910 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	10
Dann	Benign	0.32

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: rs2292186; hg19: chr19-51358394; COSMIC: COSV58101141; COSMIC: COSV58101141;