Genetic Variant NM_015488.5:c.26C>A (chr2-218270561-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_015488.5(PNKD):c.26C>A(p.Ala9Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,067,808 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A9V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

PNKD
NM_015488.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.51

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-218270561-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKD	NM_015488.5 link	c.26C>A	p.Ala9Glu	missense_variant	Exon 1 of 10	ENST00000273077.9	NP_056303.3	Q8N490-1A0A024R415
PNKD	NM_001077399.3 link	c.26C>A	p.Ala9Glu	missense_variant	Exon 1 of 3		NP_001070867.1	Q8N490-2
PNKD	XM_017003771.2 link	c.26C>A	p.Ala9Glu	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.26C>A	p.Ala9Glu	missense_variant	Exon 1 of 10	1	NM_015488.5	ENSP00000273077.4		Q8N490-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000187

AC:

AN:

1067808

Hom.:

Cov.:

AF XY:

0.00000391

AC XY:

AN XY:

511360

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:

22650

American (AMR)

AF:

0.00

AC:

AN:

12128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14458

East Asian (EAS)

AF:

0.00

AC:

AN:

27738

South Asian (SAS)

AF:

0.00

AC:

AN:

27438

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4476

European-Non Finnish (NFE)

AF:

0.00000114

AC:

AN:

877654

Other (OTH)

AF:

0.0000232

AC:

AN:

43170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.79

T;T

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.69

N;N

PhyloP100

1.5

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.042

D;D

Polyphen

1.0

D;D

Vest4

0.73

MutPred

0.38

Gain of catalytic residue at A9 (P = 0.021);Gain of catalytic residue at A9 (P = 0.021);

MVP

0.83

MPC

0.50

ClinPred

0.97

GERP RS

5.4

PromoterAI

-0.0030

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.67

gMVP

0.72

Mutation Taster

=26/74

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over