dbSNP rs150402000: PNKD:p.Arg85His (chr2-218339800-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_015488.5(PNKD):c.254G>A(p.Arg85His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,612,962 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R85C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

PNKD
NM_015488.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.25

Publications

6 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021601409).

BP6

Variant 2-218339800-G-A is Benign according to our data. Variant chr2-218339800-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 334309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 200 AD gene.

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.254G>A	p.Arg85His	missense	Exon 3 of 10	NP_056303.3
PNKD	NM_022572.4		c.182G>A	p.Arg61His	missense	Exon 2 of 9	NP_072094.1	Q8N490-3
CATIP-AS2	NR_125777.1		n.120+11360C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNKD	ENST00000273077.9	TSL:1 MANE Select	c.254G>A	p.Arg85His	missense	Exon 3 of 10	ENSP00000273077.4	Q8N490-1
PNKD	ENST00000258362.7	TSL:1	c.182G>A	p.Arg61His	missense	Exon 2 of 9	ENSP00000258362.3	Q8N490-3
PNKD	ENST00000685415.1		c.371G>A	p.Arg124His	missense	Exon 4 of 11	ENSP00000510415.1	A0A8I5KXK0

Frequencies

GnomAD3 genomes

AF:

0.00132

AC:

200

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00413

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00160

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00139

AC:

348

AN:

250912

AF XY:

0.00129

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.00224

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.00149

AC:

2174

AN:

1461026

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1073

AN XY:

726854

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33454

American (AMR)

AF:

0.00103

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.000186

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00191

AC:

102

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00175

AC:

1943

AN:

1111284

Other (OTH)

AF:

0.00104

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

103

206

309

412

515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.00132

AC:

200

AN:

151936

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74164

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

41356

American (AMR)

AF:

0.00413

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00160

AC:

109

AN:

67966

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00154

Hom.:

Bravo

AF:

0.00128

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00143

AC:

173

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00136

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (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

0.12

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.083

MetaRNN

Benign

0.022

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

0.34

PhyloP100

3.3

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.41

Sift

Benign

0.051

Sift4G

Benign

0.39

Polyphen

0.65

Vest4

0.42

MVP

0.82

MPC

0.21

ClinPred

0.028

GERP RS

5.3

Varity_R

0.067

gMVP

0.58

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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