rs141251138

Variant names:

• chr19-49865127-C-A
• NM_007254.4:c.498G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49865127-C-A
• chr19-49865127-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007254.4(PNKP):​c.498G>T​(p.Lys166Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNKP NM_007254.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, 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	c.498G>T	p.Lys166Asn	missense_variant, splice_region_variant	Exon 4 of 17	ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.498G>T	p.Lys166Asn	missense_variant, splice_region_variant	Exon 4 of 17	1	NM_007254.4	ENSP00000323511.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 12 Uncertain:1

Mar 11, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is not present in population databases (gnomAD no frequency). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1062350). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 166 of the PNKP protein (p.Lys166Asn). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;D;T;D;T;.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D;.;T;T;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Pathogenic	3.0	.;M;.;M;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.4	.;D;.;.;.;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	.;D;.;.;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;T;.;.
Polyphen		1.0	.;D;.;D;.;.;.
Vest4		0.80
MutPred		0.62		Loss of ubiquitination at K166 (P = 0.013);Loss of ubiquitination at K166 (P = 0.013);Loss of ubiquitination at K166 (P = 0.013);Loss of ubiquitination at K166 (P = 0.013);Loss of ubiquitination at K166 (P = 0.013);Loss of ubiquitination at K166 (P = 0.013);Loss of ubiquitination at K166 (P = 0.013);
MVP		0.81
MPC		0.51
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.87
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.70		Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50368384;