Variant rs761519363 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015488.5(PNKD):c.585del(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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

PNKD
NM_015488.5 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.03

Variant links:

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]

PNKD links:

CATIP-AS2 (HGNC:41079): (CATIP antisense RNA 2)

CATIP-AS2 links:

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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 linkuse as main transcript	c.585del	p.Ser196AlafsTer77	frameshift_variant	6/10	ENST00000273077.9
CATIP-AS2	NR_125777.1 linkuse as main transcript	n.120+9568del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKD	ENST00000273077.9 linkuse as main transcript	c.585del	p.Ser196AlafsTer77	frameshift_variant	6/10	1	NM_015488.5		Q8N490-1
CATIP-AS2	ENST00000411433.1 linkuse as main transcript	n.120+9568del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000378

AC:

AN:

211762

Hom.:

AF XY:

0.0000436

AC XY:

AN XY:

114676

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000864

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

207

AN:

1441824

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

102

AN XY:

715472

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000186

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000416

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over