Genetic Variant PNKD:p.Asn181Lys (chr2-218341552-C-A) – 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.543C>A(p.Asn181Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,878 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. N181H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PNKD
NM_015488.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.599

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, 0.896

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNKD	NM_015488.5	MANE Select	c.543C>A	p.Asn181Lys	missense	Exon 6 of 10	NP_056303.3
PNKD	NM_022572.4		c.471C>A	p.Asn157Lys	missense	Exon 5 of 9	NP_072094.1	Q8N490-3
CATIP-AS2	NR_125777.1		n.120+9608G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNKD	ENST00000273077.9	TSL:1 MANE Select	c.543C>A	p.Asn181Lys	missense	Exon 6 of 10	ENSP00000273077.4	Q8N490-1
PNKD	ENST00000258362.7	TSL:1	c.471C>A	p.Asn157Lys	missense	Exon 5 of 9	ENSP00000258362.3	Q8N490-3
PNKD	ENST00000685415.1		c.660C>A	p.Asn220Lys	missense	Exon 7 of 11	ENSP00000510415.1	A0A8I5KXK0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448878

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719468

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33192

American (AMR)

AF:

0.00

AC:

AN:

43672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25820

East Asian (EAS)

AF:

0.00

AC:

AN:

39058

South Asian (SAS)

AF:

0.00

AC:

AN:

83762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5372

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106180

Other (OTH)

AF:

0.00

AC:

AN:

59788

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Pathogenic

0.99

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.34

MutationAssessor

Pathogenic

3.4

PhyloP100

0.60

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.93

MutPred

0.62

Gain of glycosylation at N181 (P = 0.0198)

MVP

0.85

MPC

0.67

ClinPred

0.99

GERP RS

2.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.96

gMVP

0.94

Mutation Taster

=34/66

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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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