rs761519363
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_015488.5(PNKD):βc.585delβ(p.Ser196AlafsTer77) variant causes a frameshift change. The variant allele was found at a frequency of 0.000134 in 1,594,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000039 ( 0 hom., cov: 32)
Exomes π: 0.00014 ( 0 hom. )
Consequence
PNKD
NM_015488.5 frameshift
NM_015488.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.03
Genes affected
PNKD (HGNC:9153): (PNKD metallo-beta-lactamase domain containing) This gene is thought to play a role in the regulation of myofibrillogenesis. Mutations in this gene have been associated with the movement disorder paroxysmal non-kinesigenic dyskinesia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNKD | NM_015488.5 | c.585del | p.Ser196AlafsTer77 | frameshift_variant | 6/10 | ENST00000273077.9 | |
CATIP-AS2 | NR_125777.1 | n.120+9568del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNKD | ENST00000273077.9 | c.585del | p.Ser196AlafsTer77 | frameshift_variant | 6/10 | 1 | NM_015488.5 | ||
CATIP-AS2 | ENST00000411433.1 | n.120+9568del | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152174Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
6
AN:
152174
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000378 AC: 8AN: 211762Hom.: 0 AF XY: 0.0000436 AC XY: 5AN XY: 114676
GnomAD3 exomes
AF:
AC:
8
AN:
211762
Hom.:
AF XY:
AC XY:
5
AN XY:
114676
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000144 AC: 207AN: 1441824Hom.: 0 Cov.: 31 AF XY: 0.000143 AC XY: 102AN XY: 715472
GnomAD4 exome
AF:
AC:
207
AN:
1441824
Hom.:
Cov.:
31
AF XY:
AC XY:
102
AN XY:
715472
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74460
GnomAD4 genome
?
AF:
AC:
6
AN:
152292
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
74460
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Paroxysmal nonkinesigenic dyskinesia 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 19, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | PNKD NM_015488.4 exon 6 p.Ser196Alafs*77 (c.585del): This variant has not been reported in the literature but is present in 0.007% (5/68008) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-218341591-CG-C?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:523930). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a deletion of a single nucleotide at position 585 and creates a premature stop codon 77 amino acids downstream from this location which results in an absent or abnormal protein. However, there is insufficient evidence to establish loss of function (LOF) as a mechanism of disease for this gene at this time. In summary, data on this variant is suspicious for disease, but requires further evidence for pathogenicity. Therefore, the clinical significance of this variant is uncertain. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 08, 2022 | Variant summary: PNKD c.585delG (p.Ser196AlafsX77) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.8e-05 in 211762 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.585delG in individuals affected with Paroxysmal Nonkinesigenic Dyskinesia 1 and no experimental evidence demonstrating its impact on protein function have been reported. To our knowledge, loss of function variants in PNKD have not been associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 13, 2017 | The c.585delG variant in the PNKD gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.585delG variant causes a frameshift starting with codon Serine 196, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 77 of the new reading frame, denoted p.Ser196AlafsX77. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.585delG variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016). To date, only a few common missense variants in the PNKD gene have been published (Spacey and Adams, 2011; Stenson et al., 2014). Additionally, non-segregation with disease has been observed in one family at GeneDx. Therefore, we interpret c.585delG as a variant of uncertain significance. - |
Paroxysmal nonkinesigenic dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change creates a premature translational stop signal (p.Ser196Alafs*77) in the PNKD gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in PNKD cause disease. This variant is present in population databases (rs761519363, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PNKD-related conditions. ClinVar contains an entry for this variant (Variation ID: 523930). 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
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at