rs587784365

Variant names:

• chr19-49861800-T-TGTTGTCGATGGCGACCC
• rs587784365
• NM_007254.4:c.1253_1269dupGGGTCGCCATCGACAAC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_007254.4(PNKP):​c.1253_1269dupGGGTCGCCATCGACAAC​(p.Thr424GlyfsTer49) variant causes a frameshift change. The variant allele was found at a frequency of 0.000297 in 1,574,586 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: PNKP NM_007254.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 5.04
• Publications: 21 publications found

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: Laboratory for Molecular Medicine, G2P, Orphanet
• microcephaly, seizures, and developmental delay

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-49861800-T-TGTTGTCGATGGCGACCC is Pathogenic according to our data. Variant chr19-49861800-T-TGTTGTCGATGGCGACCC is described in ClinVar as Pathogenic. ClinVar VariationId is 4847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007254.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	NM_007254.4	MANE Select	c.1253_1269dupGGGTCGCCATCGACAAC	p.Thr424GlyfsTer49	frameshift	Exon 14 of 17	NP_009185.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	ENST00000322344.8	TSL:1 MANE Select	c.1253_1269dupGGGTCGCCATCGACAAC	p.Thr424GlyfsTer49	frameshift	Exon 14 of 17	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.1253_1269dupGGGTCGCCATCGACAAC	p.Thr424GlyfsTer49	frameshift	Exon 13 of 16	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*1180_*1196dupGGGTCGCCATCGACAAC		non_coding_transcript_exon	Exon 13 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.000185 AC: 28 AN: 151534 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000169 AC: 32 AN: 189632 AF XY: 0.000204

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000309 AC: 440 AN: 1422936 Hom.: 0 Cov.: 38 AF XY: 0.000292 AC XY: 206 AN XY: 705416

African (AFR) AF: 0.0000313 AC: 1 AN: 32000

American (AMR) AF: 0.000182 AC: 7 AN: 38494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25684

East Asian (EAS) AF: 0.00 AC: 0 AN: 36762

South Asian (SAS) AF: 0.00 AC: 0 AN: 81792

European-Finnish (FIN) AF: 0.0000212 AC: 1 AN: 47216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.000386 AC: 423 AN: 1096188

Other (OTH) AF: 0.000135 AC: 8 AN: 59066

GnomAD4 genome AF: 0.000185 AC: 28 AN: 151650 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74146

African (AFR) AF: 0.0000244 AC: 1 AN: 41030

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000383 AC: 26 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000144 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
6	-	-	Microcephaly, seizures, and developmental delay (6)
1	-	-	Abnormality of the nervous system (1)
1	-	-	Ataxia - oculomotor apraxia type 4 (1)
1	-	-	Developmental and epileptic encephalopathy, 12 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
1	-	-	Seizure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587784365; hg19: chr19-50365057;