2-218344559-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000273077.9(PNKD):​c.973C>T​(p.Arg325Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000271 in 1,587,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R325H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

PNKD
ENST00000273077.9 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.52
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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14347914).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PNKDNM_015488.5 linkuse as main transcriptc.973C>T p.Arg325Cys missense_variant 9/10 ENST00000273077.9 NP_056303.3
CATIP-AS2NR_125777.1 linkuse as main transcriptn.120+6601G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PNKDENST00000273077.9 linkuse as main transcriptc.973C>T p.Arg325Cys missense_variant 9/101 NM_015488.5 ENSP00000273077 Q8N490-1
CATIP-AS2ENST00000411433.1 linkuse as main transcriptn.120+6601G>A intron_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152150
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000446
AC:
9
AN:
201948
Hom.:
0
AF XY:
0.0000643
AC XY:
7
AN XY:
108854
show subpopulations
Gnomad AFR exome
AF:
0.000166
Gnomad AMR exome
AF:
0.0000357
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000274
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000230
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000244
AC:
35
AN:
1434836
Hom.:
0
Cov.:
31
AF XY:
0.0000253
AC XY:
18
AN XY:
711722
show subpopulations
Gnomad4 AFR exome
AF:
0.0000304
Gnomad4 AMR exome
AF:
0.0000254
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000131
Gnomad4 SAS exome
AF:
0.0000120
Gnomad4 FIN exome
AF:
0.0000389
Gnomad4 NFE exome
AF:
0.0000209
Gnomad4 OTH exome
AF:
0.0000337
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152268
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000567
ESP6500AA
AF:
0.000228
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000331
AC:
4
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 06, 2021The c.973C>T (p.R325C) alteration is located in exon 9 (coding exon 9) of the PNKD gene. This alteration results from a C to T substitution at nucleotide position 973, causing the arginine (R) at amino acid position 325 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Paroxysmal nonkinesigenic dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 18, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PNKD protein function. ClinVar contains an entry for this variant (Variation ID: 241062). This variant has not been reported in the literature in individuals affected with PNKD-related conditions. This variant is present in population databases (rs149750691, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 325 of the PNKD protein (p.Arg325Cys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.091
T
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;.;.
Eigen
Benign
-0.092
Eigen_PC
Benign
0.093
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.078
D
MetaRNN
Benign
0.14
T;T;T
MetaSVM
Uncertain
0.076
D
MutationAssessor
Benign
0.72
N;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-3.7
D;D;D
REVEL
Uncertain
0.38
Sift
Benign
0.075
T;T;T
Sift4G
Benign
0.12
T;T;T
Polyphen
0.13
B;B;.
Vest4
0.46
MVP
0.73
MPC
0.20
ClinPred
0.14
T
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.13
gMVP
0.35

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs149750691; hg19: chr2-219209282; API