19-49865209-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_007254.4(PNKP):​c.416G>A​(p.Arg139His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,614,214 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0030 ( 7 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:9

Conservation

PhyloP100: 0.160
Variant links:
Genes affected
PNKP (HGNC:9154): (polynucleotide kinase 3'-phosphatase) This locus represents a gene involved in DNA repair. In response to ionizing radiation or oxidative damage, the protein encoded by this locus catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids. Mutations at this locus have been associated with microcephaly, seizures, and developmental delay.[provided by RefSeq, Sep 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0042013526).
BP6
Variant 19-49865209-C-T is Benign according to our data. Variant chr19-49865209-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159794.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=6, Benign=1}. Variant chr19-49865209-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00182 (277/152346) while in subpopulation NFE AF= 0.00287 (195/68032). AF 95% confidence interval is 0.00254. There are 0 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PNKPNM_007254.4 linkuse as main transcriptc.416G>A p.Arg139His missense_variant 4/17 ENST00000322344.8 NP_009185.2 Q96T60-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PNKPENST00000322344.8 linkuse as main transcriptc.416G>A p.Arg139His missense_variant 4/171 NM_007254.4 ENSP00000323511.2 Q96T60-1

Frequencies

GnomAD3 genomes
AF:
0.00182
AC:
277
AN:
152228
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000699
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00196
Gnomad ASJ
AF:
0.00230
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00287
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.00194
AC:
487
AN:
251392
Hom.:
2
AF XY:
0.00218
AC XY:
296
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.000984
Gnomad AMR exome
AF:
0.000723
Gnomad ASJ exome
AF:
0.00109
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00193
Gnomad FIN exome
AF:
0.000601
Gnomad NFE exome
AF:
0.00308
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.00304
AC:
4437
AN:
1461868
Hom.:
7
Cov.:
34
AF XY:
0.00295
AC XY:
2148
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.000418
Gnomad4 AMR exome
AF:
0.000894
Gnomad4 ASJ exome
AF:
0.00157
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00185
Gnomad4 FIN exome
AF:
0.000487
Gnomad4 NFE exome
AF:
0.00362
Gnomad4 OTH exome
AF:
0.00197
GnomAD4 genome
AF:
0.00182
AC:
277
AN:
152346
Hom.:
0
Cov.:
32
AF XY:
0.00164
AC XY:
122
AN XY:
74498
show subpopulations
Gnomad4 AFR
AF:
0.000697
Gnomad4 AMR
AF:
0.00196
Gnomad4 ASJ
AF:
0.00230
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00186
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.00287
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00279
Hom.:
2
Bravo
AF:
0.00207
TwinsUK
AF:
0.00297
AC:
11
ALSPAC
AF:
0.00259
AC:
10
ESP6500AA
AF:
0.00113
AC:
5
ESP6500EA
AF:
0.00291
AC:
25
ExAC
AF:
0.00201
AC:
244
EpiCase
AF:
0.00311
EpiControl
AF:
0.00332

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024PNKP: BP4, BS2 -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Dec 14, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 28, 2016- -
Likely benign, criteria provided, single submitterclinical testingGeneDxApr 15, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicApr 15, 2020- -
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsOct 24, 2018- -
Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoOct 24, 2018PNKP NM_007254.3 exon 4 p.Arg139His (c.416G>A): This variant has not been reported in the literature and is present in 0.3% (379/126666) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-50368466-C-T). This variant is present in ClinVar (Variation ID:159794). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 23, 2017- -
Microcephaly, seizures, and developmental delay Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, no assertion criteria providedresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaDec 12, 2014The heterozygous variant (c.416G>A; p.Arg139His) in the PNKP gene observed in this patient has not been associated with disease. It occurs at low frequencies in control population (0.2% in ExAC) and a second rare variant was not observed on the other allele. This variant is considered a variant of unknown significance. -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 13, 2020- -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 10, 2023Variant summary: PNKP c.416G>A (p.Arg139His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251392 control chromosomes in the gnomAD database, including 2 homozygotes. To our knowledge, c.416G>A has not been reported in the literature in individuals affected with PNKP-Related Disorders and no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23833122, 34009545). 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS (n=6), likely benign (n=6), benign (n=1)). Based on the evidence outlined above, the variant was classified as likely benign. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 08, 2019The p.R139H variant (also known as c.416G>A), located in coding exon 3 of the PNKP gene, results from a G to A substitution at nucleotide position 416. The arginine at codon 139 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
PNKP-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 27, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Charcot-Marie-Tooth disease type 2B2;C3150667:Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoNov 11, 2021PNKP NM_007254.3 exon 4 p.Arg139His (c.416G>A): This variant has not been reported in the literature and is present in 0.3% (379/126666) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-50368466-C-T). This variant is present in ClinVar (Variation ID:159794). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Developmental and epileptic encephalopathy, 12 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.033
T;T;T;T;T;.;T
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.61
FATHMM_MKL
Benign
0.062
N
LIST_S2
Uncertain
0.93
D;.;D;D;D;D;D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.0042
T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.6
.;M;.;M;.;.;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.71
.;N;.;.;.;.;.
REVEL
Benign
0.059
Sift
Benign
0.23
.;T;.;.;.;.;.
Sift4G
Benign
0.076
T;T;T;T;T;.;.
Polyphen
0.82
.;P;.;P;.;.;.
Vest4
0.22
MVP
0.55
MPC
0.20
ClinPred
0.0099
T
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.064
gMVP
0.27

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34472250; hg19: chr19-50368466; COSMIC: COSV55586208; COSMIC: COSV55586208; API