Genetic Variant PNKD:p.Arg22Leu (chr2-218270600-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_015488.5(PNKD):c.65G>T(p.Arg22Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R22Q) 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, splice_region

Scores

Splicing: ADA: 0.9880

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.33

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	NM_015488.5	MANE Select	c.65G>T	p.Arg22Leu	missense splice_region	Exon 1 of 10	NP_056303.3
	PNKD	NM_001077399.3		c.65G>T	p.Arg22Leu	missense splice_region	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.65G>T	p.Arg22Leu	missense splice_region	Exon 1 of 10	ENSP00000273077.4
PNKD	ENST00000248451.7	TSL:1	c.65G>T	p.Arg22Leu	missense splice_region	Exon 1 of 3	ENSP00000248451.3
PNKD	ENST00000685415.1		c.65G>T	p.Arg22Leu	missense splice_region	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:

876320

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

421340

African (AFR)

AF:

0.00

AC:

AN:

18964

American (AMR)

AF:

0.00

AC:

AN:

10678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13182

East Asian (EAS)

AF:

0.00

AC:

AN:

26408

South Asian (SAS)

AF:

0.00

AC:

AN:

21268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4152

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

707602

Other (OTH)

AF:

0.00

AC:

AN:

36900

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.84

M_CAP

Benign

0.076

MetaRNN

Uncertain

0.55

MetaSVM

Pathogenic

0.93

MutationAssessor

Benign

0.69

PhyloP100

3.3

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.54

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.67

MutPred

0.39

Loss of disorder (P = 0.0278)

MVP

0.83

MPC

0.27

ClinPred

0.70

GERP RS

5.4

PromoterAI

0.031

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.31

gMVP

0.49

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.92

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

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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