ENST00000316562.9:c.12C>T

Variant names:

• chr20-3889112-C-T
• rs774784800
• ENST00000316562.9:c.12C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The ENST00000316562.9(PANK2):​c.12C>T​(p.Leu4Leu) variant causes a synonymous 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). Synonymous variant affecting the same amino acid position (i.e. L4L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (1 hom.)
• Consequence: PANK2 ENST00000316562.9 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.207
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -10 ACMG points.

• 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 VariationId is 286784.
• BP7: Synonymous conserved (PhyloP=-0.207 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000609 (85/1395296) while in subpopulation MID AF = 0.0048 (23/4796). AF 95% confidence interval is 0.00328. There are 1 homozygotes in GnomAdExome4. There are 46 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000316562.9. 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
	PANK2	NM_153638.4		c.12C>T	p.Leu4Leu	synonymous	Exon 1 of 7	NP_705902.2	Q9BZ23-1
	PANK2	NM_001324192.1		c.12C>T	p.Leu4Leu	synonymous	Exon 1 of 2	NP_001311121.1
	PANK2	NM_024960.6		c.-246+208C>T		intron	N/A	NP_079236.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PANK2	ENST00000316562.9	TSL:1	c.12C>T	p.Leu4Leu	synonymous	Exon 1 of 7	ENSP00000313377.4	Q9BZ23-1
	PANK2	ENST00000497424.5	TSL:2	c.-246+208C>T		intron	N/A	ENSP00000417609.1	Q9BZ23-2
	PANK2	ENST00000495692.5	TSL:3	c.-538+96C>T		intron	N/A	ENSP00000476745.1	V9GYH1

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

GnomAD2 exomes AF: 0.0000791 AC: 12 AN: 151644 AF XY: 0.0000621

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 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

African (AFR) AF: 0.000190 AC: 6 AN: 31564

American (AMR) AF: 0.000168 AC: 6 AN: 35610

Ashkenazi Jewish (ASJ) AF: 0.000361 AC: 9 AN: 24918

East Asian (EAS) AF: 0.00 AC: 0 AN: 35766

South Asian (SAS) AF: 0.0000380 AC: 3 AN: 78998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48684

Middle Eastern (MID) AF: 0.00480 AC: 23 AN: 4796

European-Non Finnish (NFE) AF: 0.0000297 AC: 32 AN: 1077198

Other (OTH) AF: 0.000104 AC: 6 AN: 57762

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

African (AFR) AF: 0.0000965 AC: 4 AN: 41466

American (AMR) AF: 0.000654 AC: 10 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Pigmentary pallidal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.8
DANN	Benign	0.73
PhyloP100		-0.21
PromoterAI		-0.021	Neutral

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