Genetic Variant PNKD:p.Thr285Ile (chr2-218343572-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015488.5(PNKD):c.854C>T(p.Thr285Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T285N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PNKD
NM_015488.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.71

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 links:

CATIP-AS2 (HGNC:41079): (CATIP antisense RNA 2)

CATIP-AS2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKD	NM_015488.5 link	c.854C>T	p.Thr285Ile	missense_variant	Exon 8 of 10	ENST00000273077.9	NP_056303.3	Q8N490-1A0A024R415

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9 link	c.854C>T	p.Thr285Ile	missense_variant	Exon 8 of 10	1	NM_015488.5	ENSP00000273077.4		Q8N490-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

247864

AF XY:

0.00000746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460456

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726384

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85866

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111326

Other (OTH)

AF:

0.00

AC:

AN:

60350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.3

M;.;.

PhyloP100

6.7

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.5

D;D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0050

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.93

MutPred

0.80

Gain of sheet (P = 0.0477);.;.;

MVP

0.83

MPC

0.64

ClinPred

0.98

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.66

gMVP

0.93

Mutation Taster

=25/75

disease causing

(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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2-218343572-C-T

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