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 ENST00000273077.9(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
ENST00000273077.9 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000273077.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PNKD	NM_015488.5	MANE Select	c.854C>T	p.Thr285Ile	missense	Exon 8 of 10	NP_056303.3
PNKD	NM_022572.4		c.782C>T	p.Thr261Ile	missense	Exon 7 of 9	NP_072094.1
CATIP-AS2	NR_125777.1		n.120+7588G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PNKD	ENST00000273077.9	TSL:1 MANE Select	c.854C>T	p.Thr285Ile	missense	Exon 8 of 10	ENSP00000273077.4
PNKD	ENST00000258362.7	TSL:1	c.782C>T	p.Thr261Ile	missense	Exon 7 of 9	ENSP00000258362.3
PNKD	ENST00000685415.1		c.971C>T	p.Thr324Ile	missense	Exon 9 of 11	ENSP00000510415.1

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 = 0.00233887), 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

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.3

PhyloP100

6.7

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0010

Polyphen

1.0

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

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