19-50856596-T-C

Variant names:

• chr19-50856596-T-C
• rs174776
• NM_001648.2:c.206+197T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
KLK3	NM_001648.2	c.206+197T>C		intron_variant	Intron 2 of 4	ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1	c.206+197T>C		intron_variant	Intron 2 of 4		NP_001025218.1
KLK3	NM_001030048.1	c.206+197T>C		intron_variant	Intron 2 of 4		NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7	c.206+197T>C		intron_variant	Intron 2 of 4	1	NM_001648.2	ENSP00000314151.1

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

African (AFR) AF: 0.906 AC: 9524 AN: 10514

American (AMR) AF: 0.775 AC: 11474 AN: 14802

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 9758 AN: 12620

East Asian (EAS) AF: 0.608 AC: 16204 AN: 26664

South Asian (SAS) AF: 0.643 AC: 24771 AN: 38554

European-Finnish (FIN) AF: 0.915 AC: 26427 AN: 28878

Middle Eastern (MID) AF: 0.748 AC: 1407 AN: 1882

European-Non Finnish (NFE) AF: 0.860 AC: 220680 AN: 256722

Other (OTH) AF: 0.822 AC: 20046 AN: 24394

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

African (AFR) AF: 0.907 AC: 37595 AN: 41460

American (AMR) AF: 0.802 AC: 12258 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2671 AN: 3468

East Asian (EAS) AF: 0.589 AC: 3016 AN: 5124

South Asian (SAS) AF: 0.618 AC: 2977 AN: 4816

European-Finnish (FIN) AF: 0.918 AC: 9733 AN: 10598

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.863 AC: 58629 AN: 67970

Other (OTH) AF: 0.828 AC: 1745 AN: 2108

Alfa AF: 0.854 Hom.: 82024

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
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs174776; hg19: chr19-51359852;