Genetic Variant NM_007254.4:c.1302C>G (chr19-49861692-G-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP3_Moderate

The NM_007254.4(PNKP):c.1302C>G(p.Tyr434*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y434Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

PNKP
NM_007254.4 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0690

Publications

0 publications found

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]

PNKP Gene-Disease associations (from GenCC):

ataxia - oculomotor apraxia type 4
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine
microcephaly, seizures, and developmental delay
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease type 2B2
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PNKP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4 link	c.1302C>G	p.Tyr434*	stop_gained	Exon 15 of 17	ENST00000322344.8	NP_009185.2	Q96T60-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8 link	c.1302C>G	p.Tyr434*	stop_gained	Exon 15 of 17	1	NM_007254.4	ENSP00000323511.2		Q96T60-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1395398

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31544

American (AMR)

AF:

0.00

AC:

AN:

35666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25104

East Asian (EAS)

AF:

0.00

AC:

AN:

35714

South Asian (SAS)

AF:

0.00

AC:

AN:

79256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5378

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078288

Other (OTH)

AF:

0.00

AC:

AN:

57876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.014

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.34

MetaRNN

Benign

0.41

PhyloP100

0.069

Sift4G

Pathogenic

0.0

Vest4

0.28

MVP

0.69

GERP RS

-0.45

PromoterAI

-0.0056

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=8/192

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.90

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over