19-47475502-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_007059.4(KPTN):c.1225C>T(p.Arg409Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000031 in 1,613,272 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
KPTN
NM_007059.4 stop_gained
NM_007059.4 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 3.79
Genes affected
KPTN (HGNC:6404): (kaptin, actin binding protein) This gene encodes a filamentous-actin-associated protein, which is involved in actin dynamics and plays an important role in neuromorphogenesis. This protein is part of the KICSTOR protein complex that localizes to lysosomes. Mutations in this gene result in an autosomal recessive form of intellectual disability. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 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 0.0656 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 19-47475502-G-A is Pathogenic according to our data. Variant chr19-47475502-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 620486.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KPTN | NM_007059.4 | c.1225C>T | p.Arg409Ter | stop_gained | 12/12 | ENST00000338134.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KPTN | ENST00000338134.8 | c.1225C>T | p.Arg409Ter | stop_gained | 12/12 | 1 | NM_007059.4 | P1 | |
ENST00000669287.1 | n.69-960G>A | intron_variant, non_coding_transcript_variant | |||||||
KPTN | ENST00000600551.1 | n.116C>T | non_coding_transcript_exon_variant | 2/2 | 5 | ||||
KPTN | ENST00000594208.5 | c.*859C>T | 3_prime_UTR_variant, NMD_transcript_variant | 13/13 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248728Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134988
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461084Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726782
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2019 | The R409X variant in the KPTN gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function through protein truncation. The R409X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R409X as a likely pathogenic variant. - |
Macrocephaly-developmental delay syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2019 | This sequence change results in a premature translational stop signal in the KPTN gene (p.Arg409*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acids of the KPTN protein. This variant is present in population databases (rs761616995, ExAC 0.006%). This variant has not been reported in the literature in individuals with KPTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 620486). Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
Vest4
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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