chr19-49866809-C-G

Variant names:

• chr19-49866809-C-G
• rs2257103
• NM_007254.4:c.151+245G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007254.4(PNKP):​c.151+245G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000223 in 448,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: PNKP NM_007254.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.99
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069598585).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	NM_007254.4	MANE Select	c.151+245G>C		intron	N/A	NP_009185.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	ENST00000322344.8	TSL:1 MANE Select	c.151+245G>C		intron	N/A	ENSP00000323511.2
	PNKP	ENST00000596014.5	TSL:1	c.151+245G>C		intron	N/A	ENSP00000472300.1
	PNKP	ENST00000593946.5	TSL:1	n.151+245G>C		intron	N/A	ENSP00000468896.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000223 AC: 1 AN: 448448 Hom.: 0 Cov.: 4 AF XY: 0.00000423 AC XY: 1 AN XY: 236290

African (AFR) AF: 0.00 AC: 0 AN: 12442

American (AMR) AF: 0.00 AC: 0 AN: 18786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13670

East Asian (EAS) AF: 0.00 AC: 0 AN: 30762

South Asian (SAS) AF: 0.00 AC: 0 AN: 45300

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1960

European-Non Finnish (NFE) AF: 0.00000373 AC: 1 AN: 268262

Other (OTH) AF: 0.00 AC: 0 AN: 25914

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.76
DANN	Benign	0.47
DEOGEN2	Benign	0.0074	T
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.070	T
PhyloP100		-2.0
GERP RS		-5.3
PromoterAI		0.031	Neutral
Mutation Taster		=100/0	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: rs2257103; hg19: chr19-50370066;