Genetic Variant PNKD:p.Arg16Lys (chr2-218270582-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015488.5(PNKD):c.47G>A(p.Arg16Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000304 in 987,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. R16G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

PNKD
NM_015488.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.08

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15745074).

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.47G>A	p.Arg16Lys	missense	Exon 1 of 10	NP_056303.3
	PNKD	NM_001077399.3		c.47G>A	p.Arg16Lys	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.47G>A	p.Arg16Lys	missense	Exon 1 of 10	ENSP00000273077.4
PNKD	ENST00000248451.7	TSL:1	c.47G>A	p.Arg16Lys	missense	Exon 1 of 3	ENSP00000248451.3
PNKD	ENST00000685415.1		c.47G>A	p.Arg16Lys	missense	Exon 1 of 11	ENSP00000510415.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000304

AC:

AN:

987006

Hom.:

Cov.:

AF XY:

0.00000423

AC XY:

AN XY:

473054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21194

American (AMR)

AF:

0.00

AC:

AN:

11456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13858

East Asian (EAS)

AF:

0.00

AC:

AN:

27216

South Asian (SAS)

AF:

0.00

AC:

AN:

24068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4344

European-Non Finnish (NFE)

AF:

0.00000372

AC:

AN:

806830

Other (OTH)

AF:

0.00

AC:

AN:

40586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.041

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.74

M_CAP

Benign

0.027

MetaRNN

Benign

0.16

MetaSVM

Uncertain

0.044

MutationAssessor

Benign

0.20

PhyloP100

2.1

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.11

REVEL

Benign

0.15

Sift

Benign

0.14

Sift4G

Benign

0.75

Polyphen

0.041

Vest4

0.24

MutPred

0.30

Gain of ubiquitination at R16 (P = 0.0289)

MVP

0.62

MPC

0.16

ClinPred

0.41

GERP RS

4.5

PromoterAI

0.041

Neutral

(source)

Varity_R

0.44

gMVP

0.30

Mutation Taster

=93/7

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over