19-49862432-G-T

Variant names:

• chr19-49862432-G-T
• rs372148913
• NM_007254.4:c.968C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_007254.4(PNKP):​c.968C>A​(p.Thr323Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T323M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PNKP NM_007254.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.34
• Publications: 7 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-49862432-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159803.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

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.968C>A	p.Thr323Lys	missense	Exon 11 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.968C>A	p.Thr323Lys	missense	Exon 11 of 17	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.968C>A	p.Thr323Lys	missense	Exon 10 of 16	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*895C>A		non_coding_transcript_exon	Exon 10 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1430980 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 708942

African (AFR) AF: 0.00 AC: 0 AN: 32884

American (AMR) AF: 0.00 AC: 0 AN: 40000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.00 AC: 0 AN: 38214

South Asian (SAS) AF: 0.00 AC: 0 AN: 82108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50806

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096556

Other (OTH) AF: 0.00 AC: 0 AN: 59166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		4.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.66		Gain of sheet (P = 0.0073)
MVP		0.85
MPC		0.53
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		0.94
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs372148913; hg19: chr19-50365689;