19-50855215-C-G

Variant summary

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

The NM_001648.2(KLK3):c.46+214C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 568,230 control chromosomes in the GnomAD database, including 59,414 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 0.46 (16962 hom., cov: 29)
  • Exomes 𝑓: 0.44 (42452 hom.)
• Consequence: KLK3 NM_001648.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.316

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 (AFR) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK3	NM_001648.2	c.46+214C>G		intron_variant		ENST00000326003.7
KLK3	NM_001030047.1	c.46+214C>G		intron_variant
KLK3	NM_001030048.1	c.46+214C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK3	ENST00000326003.7	c.46+214C>G		intron_variant		1	NM_001648.2	P1

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70424 AN: 151668 Hom.: 16955 Cov.: 29

Gnomad AFR AF: 0.527

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.161

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.478

Gnomad OTH AF: 0.449

GnomAD3 exomes AF: 0.388 AC: 17806 AN: 45858 Hom.: 3857 AF XY: 0.388 AC XY: 8881 AN XY: 22902

Gnomad AFR exome AF: 0.515

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.391

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.405

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.418

GnomAD4 exome AF: 0.440 AC: 183280 AN: 416446 Hom.: 42452 Cov.: 4 AF XY: 0.439 AC XY: 96083 AN XY: 218950

Gnomad4 AFR exome AF: 0.521

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.432

Gnomad4 EAS exome AF: 0.188

Gnomad4 SAS exome AF: 0.399

Gnomad4 FIN exome AF: 0.501

Gnomad4 NFE exome AF: 0.475

Gnomad4 OTH exome AF: 0.446

GnomAD4 genome AF: 0.464 AC: 70459 AN: 151784 Hom.: 16962 Cov.: 29 AF XY: 0.461 AC XY: 34227 AN XY: 74176

Gnomad4 AFR AF: 0.527

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.428

Gnomad4 EAS AF: 0.162

Gnomad4 SAS AF: 0.386

Gnomad4 FIN AF: 0.503

Gnomad4 NFE AF: 0.478

Gnomad4 OTH AF: 0.444

Alfa AF: 0.361 Hom.: 1245

Bravo AF: 0.453

Asia WGS AF: 0.281 AC: 978 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	6.0
Dann	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs266880; hg19: chr19-51358471; COSMIC: COSV58101900; COSMIC: COSV58101900;