chr19-49861257-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_007254.4(PNKP):​c.1557C>T​(p.Ser519=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000523 in 1,601,890 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00077 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

PNKP
NM_007254.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -5.19
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 -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
BP6
Variant 19-49861257-G-A is Benign according to our data. Variant chr19-49861257-G-A is described in ClinVar as [Benign]. Clinvar id is 138726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-5.19 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000768 (117/152256) while in subpopulation EAS AF= 0.0184 (95/5170). AF 95% confidence interval is 0.0154. There are 1 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PNKPNM_007254.4 linkuse as main transcriptc.1557C>T p.Ser519= synonymous_variant 17/17 ENST00000322344.8 NP_009185.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PNKPENST00000322344.8 linkuse as main transcriptc.1557C>T p.Ser519= synonymous_variant 17/171 NM_007254.4 ENSP00000323511 P1Q96T60-1

Frequencies

GnomAD3 genomes
AF:
0.000776
AC:
118
AN:
152138
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.0185
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00127
AC:
317
AN:
250454
Hom.:
2
AF XY:
0.00124
AC XY:
168
AN XY:
135634
show subpopulations
Gnomad AFR exome
AF:
0.000373
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.000199
Gnomad EAS exome
AF:
0.0162
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000354
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000497
AC:
720
AN:
1449634
Hom.:
1
Cov.:
30
AF XY:
0.000533
AC XY:
385
AN XY:
722000
show subpopulations
Gnomad4 AFR exome
AF:
0.000361
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.000115
Gnomad4 EAS exome
AF:
0.0147
Gnomad4 SAS exome
AF:
0.000279
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000627
Gnomad4 OTH exome
AF:
0.000467
GnomAD4 genome
AF:
0.000768
AC:
117
AN:
152256
Hom.:
1
Cov.:
32
AF XY:
0.000725
AC XY:
54
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.0184
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.0000893
Hom.:
0
Bravo
AF:
0.000737
Asia WGS
AF:
0.00606
AC:
21
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoSep 21, 2020- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 21, 2013This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsSep 06, 2018- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 10, 2016This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Microcephaly, seizures, and developmental delay Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Developmental and epileptic encephalopathy, 12 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.68
CADD
Benign
0.031
DANN
Benign
0.94
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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: rs142180374; hg19: chr19-50364514; API