dbSNP rs121434511: PNKD:p.Ala9Glu (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:

Genome browser will be placed here

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over