2-218344925-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3BP4BP6BS2

The NM_015488.5(PNKD):​c.1102C>T​(p.Arg368Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,614,004 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R368G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

PNKD
NM_015488.5 missense

Scores

7
10
2

Clinical Significance

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

Conservation

PhyloP100: 1.41

Publications

2 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PP3
Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, M_CAP, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.3283694).
BP6
Variant 2-218344925-C-T is Benign according to our data. Variant chr2-218344925-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1149077.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAdExome4 at 90 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PNKDNM_015488.5 linkc.1102C>T p.Arg368Trp missense_variant Exon 10 of 10 ENST00000273077.9 NP_056303.3 Q8N490-1A0A024R415

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PNKDENST00000273077.9 linkc.1102C>T p.Arg368Trp missense_variant Exon 10 of 10 1 NM_015488.5 ENSP00000273077.4 Q8N490-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152178
Hom.:
0
Cov.:
33
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:
0.000770
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000722
AC:
18
AN:
249452
AF XY:
0.0000517
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000925
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000616
AC:
90
AN:
1461708
Hom.:
0
Cov.:
33
AF XY:
0.0000550
AC XY:
40
AN XY:
727162
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33468
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.00199
AC:
79
AN:
39700
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86252
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53342
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.00000540
AC:
6
AN:
1111952
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.491
Heterozygous variant carriers
0
6
12
19
25
31
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000263
AC:
4
AN:
152296
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74472
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41568
American (AMR)
AF:
0.00
AC:
0
AN:
15296
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000772
AC:
4
AN:
5180
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68008
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.538
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00115
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000577
AC:
7
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1 Uncertain:1
Feb 02, 2023
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Paroxysmal nonkinesigenic dyskinesia Benign:1
Dec 04, 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
Pathogenic
0.74
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.59
D;.;.
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Pathogenic
0.37
D
MetaRNN
Benign
0.33
T;T;T
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Uncertain
2.8
M;.;.
PhyloP100
1.4
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-4.0
D;D;D
REVEL
Pathogenic
0.79
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.70
MVP
0.78
MPC
0.64
ClinPred
0.69
D
GERP RS
3.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.47
gMVP
0.61
Mutation Taster
=40/60
disease causing

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

Other links and lift over

dbSNP: rs185906233; hg19: chr2-219209648; API