2-218340131-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015488.5(PNKD):c.455G>A(p.Arg152Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,608,544 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R152W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 69 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 77 hom. )

Consequence

PNKD
NM_015488.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.24

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025433898).

BP6

Variant 2-218340131-G-A is Benign according to our data. Variant chr2-218340131-G-A is described in ClinVar as Benign. ClinVar VariationId is 334315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0566 is higher than 0.05.

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.455G>A	p.Arg152Gln	missense	Exon 4 of 10	NP_056303.3
PNKD	NM_022572.4		c.383G>A	p.Arg128Gln	missense	Exon 3 of 9	NP_072094.1	Q8N490-3
CATIP-AS2	NR_125777.1		n.120+11029C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNKD	ENST00000273077.9	TSL:1 MANE Select	c.455G>A	p.Arg152Gln	missense	Exon 4 of 10	ENSP00000273077.4	Q8N490-1
PNKD	ENST00000258362.7	TSL:1	c.383G>A	p.Arg128Gln	missense	Exon 3 of 9	ENSP00000258362.3	Q8N490-3
PNKD	ENST00000685415.1		c.572G>A	p.Arg191Gln	missense	Exon 5 of 11	ENSP00000510415.1	A0A8I5KXK0

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2564

AN:

151750

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0585

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00702

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0144

GnomAD2 exomes

AF:

0.00429

AC:

1074

AN:

250638

AF XY:

0.00321

show subpopulations

Gnomad AFR exome

AF:

0.0579

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00177

AC:

2583

AN:

1456674

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

1133

AN XY:

725016

show subpopulations

African (AFR)

AF:

0.0612

AC:

2041

AN:

33346

American (AMR)

AF:

0.00347

AC:

155

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.000174

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53096

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000912

AC:

101

AN:

1107628

Other (OTH)

AF:

0.00422

AC:

254

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

124

248

372

496

620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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

AF:

0.0169

AC:

2573

AN:

151870

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1237

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.0586

AC:

2423

AN:

41370

American (AMR)

AF:

0.00701

AC:

107

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

67924

Other (OTH)

AF:

0.0143

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

113

225

338

450

563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00502

Hom.:

Bravo

AF:

0.0196

ESP6500AA

AF:

0.0556

AC:

245

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00522

AC:

634

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Paroxysmal nonkinesigenic dyskinesia (1)

Paroxysmal nonkinesigenic dyskinesia 1 (1)

PNKD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.092

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.25

PhyloP100

3.2

PrimateAI

Benign

0.21

PROVEAN

Benign

1.0

REVEL

Benign

0.19

Sift

Benign

0.59

Sift4G

Benign

0.52

Polyphen

0.0030

Vest4

0.21

MVP

0.35

MPC

0.16

ClinPred

0.0090

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.039

gMVP

0.34

Mutation Taster

=98/2

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over