rs530767303

Variant names:

• chr19-49867195-C-A
• rs530767303
• NM_007254.4:c.10G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_007254.4(PNKP):​c.10G>T​(p.Val4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PNKP NM_007254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.191
• Publications: 2 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019637078).

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.10G>T	p.Val4Leu	missense	Exon 2 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.10G>T	p.Val4Leu	missense	Exon 2 of 17	ENSP00000323511.2
	PNKP	ENST00000596014.5	TSL:1	c.10G>T	p.Val4Leu	missense	Exon 1 of 16	ENSP00000472300.1
	PNKP	ENST00000593946.5	TSL:1	n.10G>T		non_coding_transcript_exon	Exon 1 of 16	ENSP00000468896.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152238 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458566 Hom.: 0 Cov.: 32 AF XY: 0.00000689 AC XY: 5 AN XY: 725440

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.000135 AC: 6 AN: 44556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5560

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110846

Other (OTH) AF: 0.0000166 AC: 1 AN: 60230

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152356 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74506

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41592

American (AMR) AF: 0.000131 AC: 2 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.5
DANN	Benign	0.77
DEOGEN2	Benign	0.0076	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.11	N
PhyloP100		-0.19
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.0060
Sift	Benign	0.82	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.15		Gain of loop (P = 0.0851)
MVP		0.22
MPC		0.087
ClinPred		0.054	T
GERP RS		-5.5
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.27
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs530767303; hg19: chr19-50370452;