chr20-3889112-C-T

Position:

• chr20-3889112-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The ENST00000702266.1(PANK2-AS1):​n.62G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000672 in 1,547,492 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (1 hom.)
• Consequence: PANK2-AS1 ENST00000702266.1 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.207

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]

PANK2-AS1 (HGNC:40732): (PANK2 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 20-3889112-C-T is Benign according to our data. Variant chr20-3889112-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286784.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PANK2-AS1	XR_001754478.3	n.62G>A		non_coding_transcript_exon_variant	1/2
PANK2	NM_153638.4	c.12C>T	p.Leu4=	synonymous_variant	1/7		NP_705902.2
PANK2	NM_001324192.1	c.12C>T	p.Leu4=	synonymous_variant	1/2		NP_001311121.1
PANK2	NM_024960.6	c.-246+208C>T		intron_variant			NP_079236.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PANK2	ENST00000316562.9	c.12C>T	p.Leu4=	synonymous_variant	1/7	1		ENSP00000313377	A2
PANK2-AS1	ENST00000702266.1	n.62G>A		non_coding_transcript_exon_variant	1/1
PANK2	ENST00000495692.5	c.-538+96C>T		intron_variant		3		ENSP00000476745
PANK2	ENST00000497424.5	c.-246+208C>T		intron_variant		2		ENSP00000417609

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000791 AC: 12 AN: 151644 Hom.: 0 AF XY: 0.0000621 AC XY: 5 AN XY: 80530

Gnomad AFR exome AF: 0.000119

Gnomad AMR exome AF: 0.000244

Gnomad ASJ exome AF: 0.000244

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000523

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000609 AC: 85 AN: 1395296 Hom.: 1 Cov.: 31 AF XY: 0.0000669 AC XY: 46 AN XY: 687954

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.000361

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000380

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000104

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74352

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	PANK2: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 05, 2016	- -

Pigmentary pallidal degeneration Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.8
DANN	Benign	0.73

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: rs774784800; hg19: chr20-3869759; COSMIC: COSV57255277; COSMIC: COSV57255277;