19-50856389-T-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001648.2(KLK3):āc.196T>Cā(p.Cys66Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 31)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
KLK3
NM_001648.2 missense
NM_001648.2 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 3.93
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KLK3 | NM_001648.2 | c.196T>C | p.Cys66Arg | missense_variant | 2/5 | ENST00000326003.7 | NP_001639.1 | |
KLK3 | NM_001030047.1 | c.196T>C | p.Cys66Arg | missense_variant | 2/5 | NP_001025218.1 | ||
KLK3 | NM_001030048.1 | c.196T>C | p.Cys66Arg | missense_variant | 2/5 | NP_001025219.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
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31
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250396Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135276
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461432Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727034
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GnomAD4 genome Cov.: 31
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Bravo
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ESP6500AA
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2022 | The c.196T>C (p.C66R) alteration is located in exon 2 (coding exon 2) of the KLK3 gene. This alteration results from a T to C substitution at nucleotide position 196, causing the cysteine (C) at amino acid position 66 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;.;D;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;T;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.;.;.;H;H;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;.;.;.;.;.;D
REVEL
Pathogenic
Sift
Pathogenic
.;D;.;.;.;.;.;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;D;.;.;.;.;.
Vest4
0.80, 0.83, 0.81, 0.80, 0.82, 0.79
MVP
MPC
0.58
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at