GeneBe

rs1553674143

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_015488.5(PNKD):​c.526G>A​(p.Asp176Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D176E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

PNKD
NM_015488.5 missense, splice_region

Scores

16
2
Splicing: ADA: 0.7428
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.99

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]
CATIP-AS2 (HGNC:41079): (CATIP antisense RNA 2)

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984

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.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PNKD
NM_015488.5
MANE Select
c.526G>Ap.Asp176Asn
missense splice_region
Exon 6 of 10NP_056303.3
PNKD
NM_022572.4
c.454G>Ap.Asp152Asn
missense splice_region
Exon 5 of 9NP_072094.1Q8N490-3
CATIP-AS2
NR_125777.1
n.120+9625C>T
intron
N/A

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PNKD
ENST00000273077.9
TSL:1 MANE Select
c.526G>Ap.Asp176Asn
missense splice_region
Exon 6 of 10ENSP00000273077.4Q8N490-1
PNKD
ENST00000258362.7
TSL:1
c.454G>Ap.Asp152Asn
missense splice_region
Exon 5 of 9ENSP00000258362.3Q8N490-3
PNKD
ENST00000685415.1
c.643G>Ap.Asp215Asn
missense splice_region
Exon 7 of 11ENSP00000510415.1A0A8I5KXK0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

ClinVar submissions
Significance:Uncertain significance
Revision:criteria provided, single submitter
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
1
-
Paroxysmal nonkinesigenic dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.91
D
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D
M_CAP
Pathogenic
0.81
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.3
H
PhyloP100
7.0
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-4.8
D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.010
D
Polyphen
0.96
D
Vest4
0.95
MutPred
0.89
Loss of catalytic residue at D176 (P = 0.026)
MVP
0.87
MPC
0.56
ClinPred
1.0
D
GERP RS
4.1
Varity_R
0.95
gMVP
0.96
Mutation Taster
=20/80
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.74
dbscSNV1_RF
Benign
0.65
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

Other links and lift over

dbSNP: rs1553674143; hg19: chr2-219206258; API