2-218341535-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_015488.5(PNKD):​c.526G>T​(p.Asp176Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000693 in 1,442,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PNKD
NM_015488.5 missense, splice_region

Scores

15
3
1
Splicing: ADA: 0.7282
1
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.99
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 made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a binding_site (size 0) in uniprot entity PNKD_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PNKDNM_015488.5 linkc.526G>T p.Asp176Tyr missense_variant, splice_region_variant Exon 6 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.526G>T p.Asp176Tyr missense_variant, splice_region_variant Exon 6 of 10 1 NM_015488.5 ENSP00000273077.4 Q8N490-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.93e-7
AC:
1
AN:
1442262
Hom.:
0
Cov.:
31
AF XY:
0.00000140
AC XY:
1
AN XY:
715498
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000193
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
D;.;.
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Pathogenic
0.81
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
4.7
H;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-8.6
D;D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
D;D;.
Vest4
0.85
MutPred
0.93
Gain of MoRF binding (P = 0.0416);.;.;
MVP
0.93
MPC
0.68
ClinPred
1.0
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.73
dbscSNV1_RF
Pathogenic
0.79
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-219206258; API