Genetic Variant PNKD:p.Val4Ala (chr2-218270546-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_015488.5(PNKD):c.11T>C(p.Val4Ala) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

Uncertain significance criteria provided, single submitter U:1

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 2 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=0.1876846).

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>C	p.Val4Ala	missense	Exon 1 of 10	NP_056303.3
	PNKD	NM_001077399.3		c.11T>C	p.Val4Ala	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>C	p.Val4Ala	missense	Exon 1 of 10	ENSP00000273077.4	Q8N490-1
PNKD	ENST00000248451.7	TSL:1	c.11T>C	p.Val4Ala	missense	Exon 1 of 3	ENSP00000248451.3	Q8N490-2
PNKD	ENST00000685415.1		c.11T>C	p.Val4Ala	missense	Exon 1 of 11	ENSP00000510415.1	A0A8I5KXK0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Paroxysmal nonkinesigenic dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.097

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.14

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.61

M_CAP

Benign

0.043

MetaRNN

Benign

0.19

MetaSVM

Uncertain

0.010

MutationAssessor

Benign

0.20

PhyloP100

1.5

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.39

REVEL

Benign

0.20

Sift

Benign

0.13

Sift4G

Benign

0.57

Polyphen

0.041

Vest4

0.48

MutPred

0.38

Loss of sheet (P = 3e-04)

MVP

0.75

MPC

0.23

ClinPred

0.28

GERP RS

3.0

PromoterAI

-0.029

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.19

gMVP

0.60

Mutation Taster

=67/33

polymorphism

(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