rs121434511

chr2-218270561-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 1.51

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 1892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKD	NM_015488.5	c.26C>T	p.Ala9Val	missense_variant	1/10	ENST00000273077.9
PNKD	NM_001077399.3	c.26C>T	p.Ala9Val	missense_variant	1/3
PNKD	XM_017003771.2	c.26C>T	p.Ala9Val	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKD	ENST00000273077.9	c.26C>T	p.Ala9Val	missense_variant	1/10	1	NM_015488.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1067812 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 511360

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.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1 Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 22, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 13, 2022	PS2, PM2, PP3, PP5 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	PNKD: PP1:Strong, PM2, PS4:Moderate, PP4, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2023	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) -

Paroxysmal dystonia;C0752210:Paroxysmal dyskinesia;C1863061:Episodic hemiplegia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 12, 2016

- -

Paroxysmal nonkinesigenic dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 02, 2022

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). 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. 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.85	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.82	A;A
PrimateAI	Uncertain	0.72	T
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	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.38
gMVP		0.61

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

Other links and lift over

dbSNP: rs121434511; hg19: chr2-219135284;