19-50907077-CAG-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_004917.5(KLK4):c.620_621delCT(p.Ser207fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
KLK4
NM_004917.5 frameshift
NM_004917.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.53
Genes affected
KLK4 (HGNC:6365): (kallikrein related peptidase 4) 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. In some tissues its expression is hormonally regulated. The expression pattern of a similar mouse protein in murine developing teeth supports a role for the protein in the degradation of enamel proteins. Several transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Dec 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.19 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-50907077-CAG-C is Pathogenic according to our data. Variant chr19-50907077-CAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1299354.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KLK4 | NM_004917.5 | c.620_621delCT | p.Ser207fs | frameshift_variant | 6/6 | ENST00000324041.6 | NP_004908.4 | |
KLK4 | NM_001302961.2 | c.335_336delCT | p.Ser112fs | frameshift_variant | 5/5 | NP_001289890.1 | ||
KLK4 | NR_126566.2 | n.609_610delCT | non_coding_transcript_exon_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KLK4 | ENST00000324041.6 | c.620_621delCT | p.Ser207fs | frameshift_variant | 6/6 | 1 | NM_004917.5 | ENSP00000326159.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250874Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135760
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461808Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727196
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Amelogenesis imperfecta type 2A1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Diagnostics Department, Viafet Genomics Laboratory | Aug 23, 2021 | As part of Carrier Screening testing performed at Viafet Genomics Laboratory, this variant was identified in a heterozygous state in a patient who is not affected with this condition. This variant is present in exon 5/5 in a position that is conserved across both transcripts of this gene (2/2). A loss-of-function variant is reported as disease-causing in HGMD and ClinVar after this position. In addition, this variant has been identified in a homozygous state in a patient affected with Amelogenesis Imperfecta. In vitro expression of the mutant protein has revealed a great reduction in protein level and absence of proteolytic activity compared to the wildtype (PMID: 26124219). - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at