dbSNP rs1553654496: 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:

Genome browser will be placed here

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PNKD	NM_015488.5 link	c.47G>A	p.Arg16Lys	missense_variant	Exon 1 of 10	ENST00000273077.9	NP_056303.3
PNKD	NM_001077399.3 link	c.47G>A	p.Arg16Lys	missense_variant	Exon 1 of 3		NP_001070867.1
PNKD	XM_017003771.2 link	c.47G>A	p.Arg16Lys	missense_variant	Exon 1 of 9		XP_016859260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9 link	c.47G>A	p.Arg16Lys	missense_variant	Exon 1 of 10	1	NM_015488.5	ENSP00000273077.4

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 v4.3

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

.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.041

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.16

T;T

MetaSVM

Uncertain

0.044

MutationAssessor

Benign

0.20

N;N

PhyloP100

2.1

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.11

N;N

REVEL

Benign

0.15

Sift

Benign

0.14

T;D

Sift4G

Benign

0.75

T;T

Polyphen

0.041

B;B

Vest4

0.24

MutPred

0.30

Gain of ubiquitination at R16 (P = 0.0289);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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over