rs142832849

chr20-3889376-G-Achr20-3889376-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000316562.9(PANK2):c.276G>A(p.Arg92=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00707 in 1,575,564 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (60 hom.)
• Consequence: PANK2 ENST00000316562.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.33

Genes affected

PANK2 (HGNC:15894): (pantothenate kinase 2) This gene encodes a protein belonging to the pantothenate kinase family and is the only member of that family to be expressed in mitochondria. Pantothenate kinase is a key regulatory enzyme in the biosynthesis of coenzyme A (CoA) in bacteria and mammalian cells. It catalyzes the first committed step in the universal biosynthetic pathway leading to CoA and is itself subject to regulation through feedback inhibition by acyl CoA species. Mutations in this gene are associated with HARP syndrome and pantothenate kinase-associated neurodegeneration (PKAN), formerly Hallervorden-Spatz syndrome. Alternative splicing, involving the use of alternate first exons, results in multiple transcripts encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 20-3889376-G-A is Benign according to our data. Variant chr20-3889376-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 444564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-3889376-G-A is described in Lovd as [Benign]. Variant chr20-3889376-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00527 (803/152380) while in subpopulation NFE AF= 0.008 (544/68038). AF 95% confidence interval is 0.00744. There are 18 homozygotes in gnomad4. There are 366 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PANK2	NM_001386393.1			upstream_gene_variant		ENST00000610179.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PANK2	ENST00000610179.7			upstream_gene_variant		1	NM_001386393.1	P2

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 803 AN: 152262 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00799

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00352 AC: 631 AN: 179352 Hom.: 2 AF XY: 0.00330 AC XY: 321 AN XY: 97374

Gnomad AFR exome AF: 0.000906

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00104

Gnomad EAS exome AF: 0.0000762

Gnomad SAS exome AF: 0.000476

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00684

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00726 AC: 10334 AN: 1423184 Hom.: 60 Cov.: 31 AF XY: 0.00691 AC XY: 4869 AN XY: 704950

Gnomad4 AFR exome AF: 0.00125

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.00175

Gnomad4 NFE exome AF: 0.00884

Gnomad4 OTH exome AF: 0.00662

GnomAD4 genome AF: 0.00527 AC: 803 AN: 152380 Hom.: 18 Cov.: 33 AF XY: 0.00491 AC XY: 366 AN XY: 74516

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00800

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00701 Hom.: 7

Bravo AF: 0.00556

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	PANK2: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Pigmentary pallidal degeneration Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	17
Dann	Uncertain	0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs142832849; hg19: chr20-3870023;