Genetic Variant PNKD:p.Val4Gly (chr2-218270546-T-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_015488.5(PNKD):c.11T>G(p.Val4Gly) 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 benign outcome for this variant. 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. V4A) 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

Not reported in ClinVar

Conservation

PhyloP100: 1.50

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.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_015488.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.382924).

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.11T>G	p.Val4Gly	missense	Exon 1 of 10	NP_056303.3
	PNKD	NM_001077399.3		c.11T>G	p.Val4Gly	missense	Exon 1 of 3	NP_001070867.1	Q8N490-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNKD	ENST00000273077.9	TSL:1 MANE Select	c.11T>G	p.Val4Gly	missense	Exon 1 of 10	ENSP00000273077.4	Q8N490-1
PNKD	ENST00000248451.7	TSL:1	c.11T>G	p.Val4Gly	missense	Exon 1 of 3	ENSP00000248451.3	Q8N490-2
PNKD	ENST00000685415.1		c.11T>G	p.Val4Gly	missense	Exon 1 of 11	ENSP00000510415.1	A0A8I5KXK0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1076540

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

516198

African (AFR)

AF:

0.00

AC:

AN:

22652

American (AMR)

AF:

0.00

AC:

AN:

11986

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14620

East Asian (EAS)

AF:

0.00

AC:

AN:

27626

South Asian (SAS)

AF:

0.00

AC:

AN:

29572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4400

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

883684

Other (OTH)

AF:

0.00

AC:

AN:

43544

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Benign

-0.024

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.62

M_CAP

Benign

0.079

MetaRNN

Benign

0.38

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

0.55

PhyloP100

1.5

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.48

Sift

Benign

0.042

Sift4G

Benign

0.13

Polyphen

0.88

Vest4

0.54

MVP

0.78

MPC

0.31

ClinPred

0.37

GERP RS

3.0

PromoterAI

-0.25

Neutral

(source)

Varity_R

0.29

gMVP

0.72

Mutation Taster

=66/34

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over