dbSNP rs775653461: PNKD:p.Met1? (chr2-218270537-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_015488.5(PNKD):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PNKD
NM_015488.5 start_lost

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.45

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 72 codons. Genomic position: 218271527. Lost 0.185 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	NM_015488.5	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	NP_056303.3
	PNKD	NM_001077399.3		c.2T>C	p.Met1?	start_lost	Exon 1 of 3	NP_001070867.1	Q8N490-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNKD	ENST00000273077.9	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	ENSP00000273077.4	Q8N490-1
PNKD	ENST00000248451.7	TSL:1	c.2T>C	p.Met1?	start_lost	Exon 1 of 3	ENSP00000248451.3	Q8N490-2
PNKD	ENST00000685415.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 11	ENSP00000510415.1	A0A8I5KXK0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

51616

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1076938

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

517730

African (AFR)

AF:

0.00

AC:

AN:

22696

American (AMR)

AF:

0.00

AC:

AN:

12464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14706

East Asian (EAS)

AF:

0.00

AC:

AN:

27950

South Asian (SAS)

AF:

0.00

AC:

AN:

31180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4448

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

880762

Other (OTH)

AF:

0.00

AC:

AN:

43586

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.63

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

PhyloP100

2.4

PROVEAN

Benign

-0.32

REVEL

Pathogenic

0.73

Sift

Uncertain

0.010

Sift4G

Uncertain

0.030

Polyphen

0.98

Vest4

0.81

MutPred

0.98

Gain of disorder (P = 0.0874)

MVP

0.86

ClinPred

1.0

GERP RS

5.4

PromoterAI

-0.81

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.90

gMVP

0.69

Mutation Taster

=45/155

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over