rs1555811171

Variant names:

• chr19-49862568-C-G
• rs1555811171
• NM_007254.4:c.906G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-49862568-C-G
• chr19-49862568-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007254.4(PNKP):​c.906G>C​(p.Lys302Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K302K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PNKP NM_007254.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.958
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4	c.906G>C	p.Lys302Asn	missense_variant	Exon 10 of 17	ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.906G>C	p.Lys302Asn	missense_variant	Exon 10 of 17	1	NM_007254.4	ENSP00000323511.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 12 Uncertain:1

Feb 18, 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 478787). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 302 of the PNKP protein (p.Lys302Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T;T;T;T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D;.;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.4	.;M;.;M;.
PhyloP100		0.96
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	.;D;.;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	.;D;.;.;.
Sift4G	Uncertain	0.015	D;D;D;D;D
Polyphen		1.0	.;D;.;D;.
Vest4		0.52
MutPred		0.54		Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);.;Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);
MVP		0.73
MPC		0.49
ClinPred		0.95	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.36
gMVP		0.73
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555811171; hg19: chr19-50365825;