chr20-3889114-G-A

Position:

chr20-3889114-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000702266.1(PANK2-AS1):n.60C>T 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 0.00000775 in 1,548,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

PANK2-AS1
ENST00000702266.1 non_coding_transcript_exon

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.970

Variant links:

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 links:

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

PANK2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029738426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein
PANK2-AS1	XR_001754478.3 linkuse as main transcript	n.60C>T		non_coding_transcript_exon_variant	1/2
PANK2	NM_153638.4 linkuse as main transcript	c.14G>A	p.Gly5Glu	missense_variant	1/7	NP_705902.2
PANK2	NM_001324192.1 linkuse as main transcript	c.14G>A	p.Gly5Glu	missense_variant	1/2	NP_001311121.1
PANK2	NM_024960.6 linkuse as main transcript	c.-246+210G>A		intron_variant		NP_079236.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	Protein	Appris	UniProt
PANK2	ENST00000316562.9 linkuse as main transcript	c.14G>A	p.Gly5Glu	missense_variant	1/7	1	ENSP00000313377	A2	Q9BZ23-1
PANK2-AS1	ENST00000702266.1 linkuse as main transcript	n.60C>T		non_coding_transcript_exon_variant	1/1
PANK2	ENST00000495692.5 linkuse as main transcript	c.-538+98G>A		intron_variant		3	ENSP00000476745
PANK2	ENST00000497424.5 linkuse as main transcript	c.-246+210G>A		intron_variant		2	ENSP00000417609		Q9BZ23-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000392

AC:

AN:

153068

Hom.:

AF XY:

0.0000246

AC XY:

AN XY:

81268

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000177

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000264

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000645

AC:

AN:

1396350

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

688526

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000168

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000615

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000374

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pigmentary pallidal degeneration

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 04, 2022

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 5 of the PANK2 protein (p.Gly5Glu). This variant is present in population databases (rs748405977, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with PANK2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.13

CADD

Benign

7.0

DANN

Benign

0.81

DEOGEN2

Benign

0.20

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.37

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.030

MetaSVM

Uncertain

-0.074

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.38

REVEL

Benign

0.17

Sift

Uncertain

0.027

Sift4G

Benign

0.11

Polyphen

0.0010

Vest4

0.15

MutPred

0.30

Loss of MoRF binding (P = 0.0143);

MVP

0.78

MPC

1.4

ClinPred

0.16

GERP RS

0.31

Varity_R

0.092

gMVP

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over