chr19-50949096-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_012427.5(KLK5):c.355G>A(p.Gly119Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,612,474 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 (★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000032 ( 0 hom. )
Consequence
KLK5
NM_012427.5 missense
NM_012427.5 missense
Scores
12
4
3
Clinical Significance
Conservation
PhyloP100: 7.22
Genes affected
KLK5 (HGNC:6366): (kallikrein related peptidase 5) 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. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Its expression is up-regulated by estrogens and progestins. The encoded protein is secreted and may be involved in desquamation in the epidermis. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]
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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, 0.987
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000461 AC: 7AN: 151774Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000240 AC: 6AN: 249636Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135172
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GnomAD4 exome AF: 0.0000322 AC: 47AN: 1460700Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 726618
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GnomAD4 genome AF: 0.0000461 AC: 7AN: 151774Hom.: 0 Cov.: 30 AF XY: 0.0000540 AC XY: 4AN XY: 74084
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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 | Sep 30, 2024 | The c.355G>A (p.G119S) alteration is located in exon 4 (coding exon 3) of the KLK5 gene. This alteration results from a G to A substitution at nucleotide position 355, causing the glycine (G) at amino acid position 119 to be replaced by a serine (S). 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
Pathogenic
D
LIST_S2
Benign
.;.;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M;.
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.
Sift4G
Pathogenic
D;D;D;.
Polyphen
D;D;D;.
Vest4
MutPred
Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);Gain of disorder (P = 0.0766);
MVP
MPC
0.50
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