chr19-49866809-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007254.4(PNKP):​c.151+245G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 600,164 control chromosomes in the GnomAD database, including 47,556 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (12038 hom., cov: 33)
  • Exomes 𝑓: 0.39 (35518 hom.)
• Consequence: PNKP NM_007254.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.99
• Publications: 22 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.2666664E-4).
• BP6: Variant 19-49866809-C-T is Benign according to our data. Variant chr19-49866809-C-T is described in ClinVar as Benign. ClinVar VariationId is 667942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

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>A		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>A		intron	N/A	ENSP00000323511.2
	PNKP	ENST00000596014.5	TSL:1	c.151+245G>A		intron	N/A	ENSP00000472300.1
	PNKP	ENST00000593946.5	TSL:1	n.151+245G>A		intron	N/A	ENSP00000468896.1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60094 AN: 152002 Hom.: 12041 Cov.: 33

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.445

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.392 AC: 175494 AN: 448044 Hom.: 35518 Cov.: 4 AF XY: 0.399 AC XY: 94177 AN XY: 236074

African (AFR) AF: 0.422 AC: 5247 AN: 12434

American (AMR) AF: 0.303 AC: 5696 AN: 18770

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 6311 AN: 13668

East Asian (EAS) AF: 0.209 AC: 6437 AN: 30740

South Asian (SAS) AF: 0.491 AC: 22248 AN: 45266

European-Finnish (FIN) AF: 0.375 AC: 11733 AN: 31316

Middle Eastern (MID) AF: 0.485 AC: 951 AN: 1960

European-Non Finnish (NFE) AF: 0.398 AC: 106730 AN: 268002

Other (OTH) AF: 0.392 AC: 10141 AN: 25888

GnomAD4 genome AF: 0.395 AC: 60105 AN: 152120 Hom.: 12038 Cov.: 33 AF XY: 0.396 AC XY: 29466 AN XY: 74372

African (AFR) AF: 0.428 AC: 17756 AN: 41484

American (AMR) AF: 0.325 AC: 4975 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.445 AC: 1545 AN: 3472

East Asian (EAS) AF: 0.208 AC: 1079 AN: 5176

South Asian (SAS) AF: 0.488 AC: 2357 AN: 4826

European-Finnish (FIN) AF: 0.389 AC: 4115 AN: 10572

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26851 AN: 67976

Other (OTH) AF: 0.399 AC: 844 AN: 2116

Alfa AF: 0.389 Hom.: 4473

Bravo AF: 0.390

TwinsUK AF: 0.406 AC: 1506

ALSPAC AF: 0.395 AC: 1524

Asia WGS AF: 0.318 AC: 1108 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.88
DANN	Benign	0.85
DEOGEN2	Benign	0.0074	T
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.00053	T
PhyloP100		-2.0
GERP RS		-5.3
PromoterAI		0.037	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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;