2-218339877-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_015488.5(PNKD):c.331A>G(p.Thr111Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,548,744 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T111T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

PNKD
NM_015488.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.764

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00935021).

BP6

Variant 2-218339877-A-G is Benign according to our data. Variant chr2-218339877-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334313.

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKD	NM_015488.5 link	c.331A>G	p.Thr111Ala	missense_variant	Exon 3 of 10	ENST00000273077.9	NP_056303.3	Q8N490-1A0A024R415

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9 link	c.331A>G	p.Thr111Ala	missense_variant	Exon 3 of 10	1	NM_015488.5	ENSP00000273077.4		Q8N490-1

Frequencies

GnomAD3 genomes

AF:

0.000120

AC:

AN:

149812

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:

0.00256

Gnomad SAS

AF:

0.000213

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000447

Gnomad OTH

AF:

0.000488

GnomAD2 exomes

AF:

0.000266

AC:

AN:

165384

AF XY:

0.000282

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000375

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00263

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000439

Gnomad OTH exome

AF:

0.000219

GnomAD4 exome

AF:

0.000178

AC:

249

AN:

1398830

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

126

AN XY:

690360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31908

American (AMR)

AF:

0.0000267

AC:

AN:

37426

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23998

East Asian (EAS)

AF:

0.00544

AC:

199

AN:

36614

South Asian (SAS)

AF:

0.000129

AC:

AN:

77328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45992

Middle Eastern (MID)

AF:

0.000426

AC:

AN:

4692

European-Non Finnish (NFE)

AF:

0.0000259

AC:

AN:

1082784

Other (OTH)

AF:

0.000155

AC:

AN:

58088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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

AF:

0.000120

AC:

AN:

149914

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

AN XY:

73054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40854

American (AMR)

AF:

0.00

AC:

AN:

15102

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3434

East Asian (EAS)

AF:

0.00257

AC:

AN:

5060

South Asian (SAS)

AF:

0.000213

AC:

AN:

4698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0000447

AC:

AN:

67044

Other (OTH)

AF:

0.000483

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000859

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.000215

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1

Uncertain:1Benign:1

Nov 13, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PNKD: BS1 -

Paroxysmal nonkinesigenic dyskinesia

Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.12

T;.;.

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.64

T;T;T

MetaRNN

Benign

0.0094

T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

0.0

N;.;.

PhyloP100

0.76

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.27

N;N;N

REVEL

Benign

0.27

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.54

T;T;T

Polyphen

0.0020

B;B;.

Vest4

0.22

MVP

0.30

MPC

0.14

ClinPred

0.015

GERP RS

-0.12

Varity_R

0.035

gMVP

0.46

Mutation Taster

=96/4

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over