rs141506076

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_015488.5(PNKD):c.560G>A(p.Arg187Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,602,846 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 4 hom. )

Consequence

PNKD
NM_015488.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.12

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 made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057805777).

BP6

Variant 2-218341569-G-A is Benign according to our data. Variant chr2-218341569-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 334320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKD	NM_015488.5 linkuse as main transcript	c.560G>A	p.Arg187Gln	missense_variant	6/10	ENST00000273077.9	NP_056303.3
CATIP-AS2	NR_125777.1 linkuse as main transcript	n.120+9591C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9 linkuse as main transcript	c.560G>A	p.Arg187Gln	missense_variant	6/10	1	NM_015488.5	ENSP00000273077		Q8N490-1
CATIP-AS2	ENST00000411433.1 linkuse as main transcript	n.120+9591C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000933

AC:

142

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0108

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00584

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00162

AC:

371

AN:

228474

Hom.:

AF XY:

0.00153

AC XY:

190

AN XY:

123866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000181

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0121

Gnomad SAS exome

AF:

0.000179

Gnomad FIN exome

AF:

0.00497

Gnomad NFE exome

AF:

0.000412

Gnomad OTH exome

AF:

0.00251

GnomAD4 exome

AF:

0.000623

AC:

903

AN:

1450552

Hom.:

Cov.:

AF XY:

0.000597

AC XY:

430

AN XY:

720380

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.000183

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0118

Gnomad4 SAS exome

AF:

0.000298

Gnomad4 FIN exome

AF:

0.00498

Gnomad4 NFE exome

AF:

0.0000867

Gnomad4 OTH exome

AF:

0.000818

GnomAD4 genome

AF:

0.000932

AC:

142

AN:

152294

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

102

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0108

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00584

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000763

Hom.:

Bravo

AF:

0.000748

ExAC

AF:

0.00158

AC:

191

Asia WGS

AF:

0.00751

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2020

- -

Paroxysmal nonkinesigenic dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.23

T;.;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.82

T;T;T

MetaRNN

Benign

0.0058

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.19

N;.;.

MutationTaster

Benign

0.77

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.030

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.49

T;T;T

Sift4G

Benign

0.68

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.18

MVP

0.40

MPC

0.16

ClinPred

0.013

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.058

gMVP

0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over