19-49861227-T-G

Variant names:

• chr19-49861227-T-G
• rs201872477
• ENST00000593946.5:n.*1514A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007254.4(PNKP):​c.*21A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00721 in 1,489,272 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (70 hom.)
• Consequence: PNKP NM_007254.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.03
• Publications: 2 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 (BayesDel_noAF=-0.64).
• BP6: Variant 19-49861227-T-G is Benign according to our data. Variant chr19-49861227-T-G is described in ClinVar as [Benign]. Clinvar id is 329890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00481 (733/152288) while in subpopulation SAS AF = 0.0155 (75/4830). AF 95% confidence interval is 0.0127. There are 1 homozygotes in GnomAd4. There are 369 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 70 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4	c.*21A>C		3_prime_UTR_variant	Exon 17 of 17	ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.*21A>C		3_prime_UTR_variant	Exon 17 of 17	1	NM_007254.4	ENSP00000323511.2

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 732 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00690

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00661 AC: 1643 AN: 248644 AF XY: 0.00763

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00340

Gnomad EAS exome AF: 0.000382

Gnomad FIN exome AF: 0.00551

Gnomad NFE exome AF: 0.00661

Gnomad OTH exome AF: 0.00607

GnomAD4 exome AF: 0.00748 AC: 10001 AN: 1336984 Hom.: 70 Cov.: 20 AF XY: 0.00785 AC XY: 5270 AN XY: 671666

African (AFR) AF: 0.00142 AC: 44 AN: 30906

American (AMR) AF: 0.00334 AC: 149 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00322 AC: 82 AN: 25436

East Asian (EAS) AF: 0.000128 AC: 5 AN: 39112

South Asian (SAS) AF: 0.0186 AC: 1556 AN: 83784

European-Finnish (FIN) AF: 0.00520 AC: 275 AN: 52840

Middle Eastern (MID) AF: 0.00632 AC: 33 AN: 5220

European-Non Finnish (NFE) AF: 0.00749 AC: 7477 AN: 998880

Other (OTH) AF: 0.00676 AC: 380 AN: 56220

GnomAD4 genome AF: 0.00481 AC: 733 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.00495 AC XY: 369 AN XY: 74472

African (AFR) AF: 0.00144 AC: 60 AN: 41574

American (AMR) AF: 0.00340 AC: 52 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.0155 AC: 75 AN: 4830

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00690 AC: 469 AN: 68006

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00457

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, seizures, and developmental delay Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.012
DANN	Benign	0.78
PhyloP100		-2.0
PromoterAI		0.083	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: rs201872477; hg19: chr19-50364484;