Genetic Variant PNKD:p.Ala7Val (chr2-218270555-C-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 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

Publications

15 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 1893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015488.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	NM_015488.5	MANE Select	c.20C>T	p.Ala7Val	missense	Exon 1 of 10	NP_056303.3
	PNKD	NM_001077399.3		c.20C>T	p.Ala7Val	missense	Exon 1 of 3	NP_001070867.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PNKD	ENST00000273077.9	TSL:1 MANE Select	c.20C>T	p.Ala7Val	missense	Exon 1 of 10	ENSP00000273077.4
PNKD	ENST00000248451.7	TSL:1	c.20C>T	p.Ala7Val	missense	Exon 1 of 3	ENSP00000248451.3
PNKD	ENST00000685415.1		c.20C>T	p.Ala7Val	missense	Exon 1 of 11	ENSP00000510415.1

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

African (AFR)

AF:

0.00

AC:

AN:

22862

American (AMR)

AF:

0.00

AC:

AN:

12420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14620

East Asian (EAS)

AF:

0.00

AC:

AN:

27896

South Asian (SAS)

AF:

0.00

AC:

AN:

29172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4494

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

888702

Other (OTH)

AF:

0.00

AC:

AN:

43700

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Paroxysmal nonkinesigenic dyskinesia 1 (5)

Paroxysmal nonkinesigenic dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

0.96

MutationAssessor

Benign

0.55

PhyloP100

3.5

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.61

MutPred

0.75

Gain of sheet (P = 0.0344)

MVP

0.91

MPC

0.33

ClinPred

0.92

GERP RS

5.1

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.39

gMVP

0.48

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over