rs174776

Positions:

• chr19-50856596-T-C

Variant summary

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

The NM_001648.2(KLK3):​c.206+197T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.829 in 567,072 control chromosomes in the GnomAD database, including 197,113 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 0.85 (55720 hom., cov: 29)
  • Exomes 𝑓: 0.82 (141393 hom.)
• Consequence: KLK3 NM_001648.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.212

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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK3	NM_001648.2	c.206+197T>C		intron_variant		ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1	c.206+197T>C		intron_variant			NP_001025218.1
KLK3	NM_001030048.1	c.206+197T>C		intron_variant			NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7	c.206+197T>C		intron_variant		1	NM_001648.2	ENSP00000314151	P1

Frequencies

GnomAD3 genomes AF: 0.853 AC: 129535 AN: 151922 Hom.: 55685 Cov.: 29

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.856

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.918

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.863

Gnomad OTH AF: 0.826

GnomAD4 exome AF: 0.820 AC: 340291 AN: 415030 Hom.: 141393 Cov.: 4 AF XY: 0.810 AC XY: 176228 AN XY: 217502

Gnomad4 AFR exome AF: 0.906

Gnomad4 AMR exome AF: 0.775

Gnomad4 ASJ exome AF: 0.773

Gnomad4 EAS exome AF: 0.608

Gnomad4 SAS exome AF: 0.643

Gnomad4 FIN exome AF: 0.915

Gnomad4 NFE exome AF: 0.860

Gnomad4 OTH exome AF: 0.822

GnomAD4 genome AF: 0.853 AC: 129623 AN: 152042 Hom.: 55720 Cov.: 29 AF XY: 0.847 AC XY: 62938 AN XY: 74294

Gnomad4 AFR AF: 0.907

Gnomad4 AMR AF: 0.802

Gnomad4 ASJ AF: 0.770

Gnomad4 EAS AF: 0.589

Gnomad4 SAS AF: 0.618

Gnomad4 FIN AF: 0.918

Gnomad4 NFE AF: 0.863

Gnomad4 OTH AF: 0.828

Alfa AF: 0.853 Hom.: 60349

Bravo AF: 0.848

Asia WGS AF: 0.619 AC: 2155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.6
DANN	Benign	0.48

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: rs174776; hg19: chr19-51359852;