NM_015488.5:c.26C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_015488.5(PNKD):c.26C>T(p.Ala9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A9P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PNKD
NM_015488.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 1.51

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

paroxysmal nonkinesigenic dyskinesia 1
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
Tourette syndrome
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PNKD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-218270561-C-T is Pathogenic according to our data. Variant chr2-218270561-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKD	NM_015488.5 link	c.26C>T	p.Ala9Val	missense_variant	Exon 1 of 10	ENST00000273077.9	NP_056303.3	Q8N490-1A0A024R415
PNKD	NM_001077399.3 link	c.26C>T	p.Ala9Val	missense_variant	Exon 1 of 3		NP_001070867.1	Q8N490-2
PNKD	XM_017003771.2 link	c.26C>T	p.Ala9Val	missense_variant	Exon 1 of 9		XP_016859260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9 link	c.26C>T	p.Ala9Val	missense_variant	Exon 1 of 10	1	NM_015488.5	ENSP00000273077.4		Q8N490-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1067812

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

511360

African (AFR)

AF:

0.00

AC:

AN:

22650

American (AMR)

AF:

0.00

AC:

AN:

12128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14458

East Asian (EAS)

AF:

0.00

AC:

AN:

27738

South Asian (SAS)

AF:

0.00

AC:

AN:

27438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4476

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

877658

Other (OTH)

AF:

0.00

AC:

AN:

43170

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1

Pathogenic:3Other:1

Oct 13, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS2, PM2, PP3, PP5 -

Oct 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 22, 2023

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not provided

Pathogenic:2

May 18, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21487022, 8659518, 9490305, 16972263, 28894297, 29356177, 19124534, 33929620, 34177764, 20301400, 15824259, 32443735, 26598494, 23775978, 22989765, 29103325, 35795196, 15496428, 15262732, 16216955, 25453601) -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PNKD: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting -

Paroxysmal dystonia;C0752210:Paroxysmal dyskinesia;C1863061:Episodic hemiplegia

Pathogenic:1

Jan 12, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Paroxysmal nonkinesigenic dyskinesia

Pathogenic:1

Aug 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1892). This missense change has been observed in individuals with paroxysmal non-kinesigenic dyskinesia (PMID: 15496428). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 9 of the PNKD protein (p.Ala9Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

.;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.85

D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.69

N;N

PhyloP100

1.5

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.28

N;N

REVEL

Uncertain

0.56

Sift

Uncertain

0.021

D;D

Sift4G

Benign

0.068

T;D

Polyphen

1.0

D;D

Vest4

0.53

MutPred

0.74

Gain of catalytic residue at A9 (P = 0.0077);Gain of catalytic residue at A9 (P = 0.0077);

MVP

0.92

MPC

0.34

ClinPred

0.97

GERP RS

5.4

PromoterAI

-0.10

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.38

gMVP

0.61

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over