Genetic Variant NM_015488.5:c.20C>T (chr2-218270555-C-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_015488.5(PNKD):c.20C>T(p.Ala7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

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:5O:1

Conservation

PhyloP100: 3.52

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

PP5

Variant 2-218270555-C-T is Pathogenic according to our data. Variant chr2-218270555-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1893.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.20C>T	p.Ala7Val	missense_variant	Exon 1 of 10	ENST00000273077.9	NP_056303.3	Q8N490-1A0A024R415
PNKD	NM_001077399.3 link	c.20C>T	p.Ala7Val	missense_variant	Exon 1 of 3		NP_001070867.1	Q8N490-2
PNKD	XM_017003771.2 link	c.20C>T	p.Ala7Val	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.20C>T	p.Ala7Val	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:

1082298

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

518710

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1

Pathogenic:4Other:1

Mar 09, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Apr 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 12, 2024

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

May 25, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine (exon 1). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously described as pathogenic in multiple individuals with paroxysmal nonkinesigenic dyskinesia (PMID: 15262732, 15496428, 15824259). (P) 0901 - Strong evidence for segregation with disease. The variant has also been shown to segregate with disease in multiple families (PMID: 15262732, 15496428, 15824259). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Paroxysmal nonkinesigenic dyskinesia

Pathogenic:1

May 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PNKD function (PMID: 19124534, 21487022). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1893). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 7 of the PNKD protein (p.Ala7Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paroxysmal non-kinesigenic dyskinesia or paroxysmal dystonic choreoathetosis (PMID: 15262732, 15496428, 22967746, 25107857). It has also been observed to segregate with disease in related individuals. This variant is also known as 66C>T. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

.;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.85

T;T

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Benign

0.55

N;N

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.61

MutPred

0.75

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.91

MPC

0.33

ClinPred

0.92

GERP RS

5.1

Varity_R

0.39

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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