rs145307985

Variant names:

• chr19-49863722-C-T
• rs145307985
• NM_007254.4:c.783G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007254.4(PNKP):​c.783G>A​(p.Pro261Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00511 in 1,558,080 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (24 hom.)
• Consequence: PNKP NM_007254.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.90
• Publications: 3 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: Laboratory for Molecular Medicine, G2P, Orphanet
• microcephaly, seizures, and developmental delay

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 19-49863722-C-T is Benign according to our data. Variant chr19-49863722-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00351 (535/152284) while in subpopulation NFE AF = 0.00594 (404/68010). AF 95% confidence interval is 0.00546. There are 2 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.783G>A	p.Pro261Pro	synonymous	Exon 8 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.783G>A	p.Pro261Pro	synonymous	Exon 8 of 17	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.783G>A	p.Pro261Pro	synonymous	Exon 7 of 16	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*710G>A		non_coding_transcript_exon	Exon 7 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 535 AN: 152166 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00594

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00280 AC: 459 AN: 164102 AF XY: 0.00272

Gnomad AFR exome AF: 0.000954

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.000933

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000577

Gnomad NFE exome AF: 0.00544

Gnomad OTH exome AF: 0.00510

GnomAD4 exome AF: 0.00528 AC: 7425 AN: 1405796 Hom.: 24 Cov.: 31 AF XY: 0.00509 AC XY: 3533 AN XY: 694180

African (AFR) AF: 0.000809 AC: 26 AN: 32150

American (AMR) AF: 0.00278 AC: 101 AN: 36366

Ashkenazi Jewish (ASJ) AF: 0.000753 AC: 19 AN: 25230

East Asian (EAS) AF: 0.00 AC: 0 AN: 36646

South Asian (SAS) AF: 0.000388 AC: 31 AN: 79938

European-Finnish (FIN) AF: 0.000713 AC: 35 AN: 49092

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5692

European-Non Finnish (NFE) AF: 0.00643 AC: 6957 AN: 1082482

Other (OTH) AF: 0.00424 AC: 247 AN: 58200

GnomAD4 genome AF: 0.00351 AC: 535 AN: 152284 Hom.: 2 Cov.: 33 AF XY: 0.00304 AC XY: 226 AN XY: 74460

African (AFR) AF: 0.00115 AC: 48 AN: 41560

American (AMR) AF: 0.00451 AC: 69 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00594 AC: 404 AN: 68010

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00452 Hom.: 1

Bravo AF: 0.00389

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Microcephaly, seizures, and developmental delay (3)
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 12 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.1
DANN	Benign	0.80
PhyloP100		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs145307985; hg19: chr19-50366979; COSMIC: COSV106372194; COSMIC: COSV106372194;