chr19-49861233-G-A

Variant summary

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

The NM_007254.4(PNKP):​c.*15C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,505,468 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0056 ( 5 hom., cov: 32)
Exomes 𝑓: 0.00054 ( 11 hom. )

Consequence

PNKP
NM_007254.4 3_prime_UTR

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.517
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 (BayesDel_noAF=-0.77).
BP6
Variant 19-49861233-G-A is Benign according to our data. Variant chr19-49861233-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138727.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00559 (852/152316) while in subpopulation AFR AF= 0.0197 (821/41570). AF 95% confidence interval is 0.0186. There are 5 homozygotes in gnomad4. There are 371 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PNKPNM_007254.4 linkuse as main transcriptc.*15C>T 3_prime_UTR_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.*15C>T 3_prime_UTR_variant 17/171 NM_007254.4 ENSP00000323511 P1Q96T60-1

Frequencies

GnomAD3 genomes
AF:
0.00558
AC:
849
AN:
152198
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0197
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.00134
AC:
333
AN:
249132
Hom.:
5
AF XY:
0.000924
AC XY:
125
AN XY:
135234
show subpopulations
Gnomad AFR exome
AF:
0.0197
Gnomad AMR exome
AF:
0.000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000891
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.000537
AC:
726
AN:
1353152
Hom.:
11
Cov.:
21
AF XY:
0.000423
AC XY:
287
AN XY:
678854
show subpopulations
Gnomad4 AFR exome
AF:
0.0203
Gnomad4 AMR exome
AF:
0.000605
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000832
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000789
Gnomad4 OTH exome
AF:
0.000861
GnomAD4 genome
AF:
0.00559
AC:
852
AN:
152316
Hom.:
5
Cov.:
32
AF XY:
0.00498
AC XY:
371
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.0197
Gnomad4 AMR
AF:
0.00131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00237
Alfa
AF:
0.00224
Hom.:
1
Bravo
AF:
0.00637
Asia WGS
AF:
0.00144
AC:
5
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Microcephaly, seizures, and developmental delay Uncertain:1Benign:1
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoFeb 08, 2013- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxApr 12, 2012This 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. -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 30, 2017This alteration is classified as likely benign based on a combination of the following: 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.77
CADD
Benign
2.0
DANN
Benign
0.90
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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: rs1050332; hg19: chr19-50364490; API