chr19-49862520-A-AG

Variant names:

• chr19-49862520-A-AG
• rs3739200
• NM_007254.4:c.936+17dupC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_007254.4(PNKP):​c.936+17dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,605,176 control chromosomes in the GnomAD database, including 169 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (23 hom., cov: 32)
  • Exomes 𝑓: 0.012 (146 hom.)
• Consequence: PNKP NM_007254.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.889
• 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: Ambry Genetics, ClinGen, 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 -9 ACMG points.

• BP6: Variant 19-49862520-A-AG is Benign according to our data. Variant chr19-49862520-A-AG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206371.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0106 (1608/152224) while in subpopulation AMR AF = 0.0286 (438/15300). AF 95% confidence interval is 0.0264. There are 23 homozygotes in GnomAd4. There are 759 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.936+17dupC		intron	N/A	NP_009185.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	ENST00000322344.8	TSL:1 MANE Select	c.936+17_936+18insC		intron	N/A	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.936+17_936+18insC		intron	N/A	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*863+17_*863+18insC		intron	N/A	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1612 AN: 152106 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0109 AC: 2507 AN: 229218 AF XY: 0.0113

Gnomad AFR exome AF: 0.00219

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0307

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.0127

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0123 AC: 17873 AN: 1452952 Hom.: 146 Cov.: 35 AF XY: 0.0124 AC XY: 8938 AN XY: 722230

African (AFR) AF: 0.00270 AC: 90 AN: 33298

American (AMR) AF: 0.0180 AC: 783 AN: 43512

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 804 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39280

South Asian (SAS) AF: 0.00601 AC: 512 AN: 85236

European-Finnish (FIN) AF: 0.00160 AC: 84 AN: 52466

Middle Eastern (MID) AF: 0.0391 AC: 225 AN: 5750

European-Non Finnish (NFE) AF: 0.0131 AC: 14542 AN: 1107590

Other (OTH) AF: 0.0139 AC: 833 AN: 59930

GnomAD4 genome AF: 0.0106 AC: 1608 AN: 152224 Hom.: 23 Cov.: 32 AF XY: 0.0102 AC XY: 759 AN XY: 74412

African (AFR) AF: 0.00233 AC: 97 AN: 41546

American (AMR) AF: 0.0286 AC: 438 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4828

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 897 AN: 67976

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.0137 Hom.: 3

Bravo AF: 0.0116

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	Developmental and epileptic encephalopathy, 12 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.89
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: rs3739200; hg19: chr19-50365777;