dbSNP rs535092413: PANK4:p.Asp701Asn (chr1-2509869-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_018216.4(PANK4):c.2101G>A(p.Asp701Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000701 in 1,611,644 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 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

PANK4
NM_018216.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.02

Publications

0 publications found

Variant links:

Genes affected

PANK4 (HGNC:19366): (pantothenate kinase 4 (inactive)) This gene encodes a protein belonging to the pantothenate kinase family. 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 CoA. This family member is most abundant in muscle but is expressed in all tissues. [provided by RefSeq, Jul 2008]

PANK4 Gene-Disease associations (from GenCC):

early-onset posterior polar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cataract
Inheritance: AD Classification: LIMITED Submitted by: G2P
cataract 49
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PANK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.38800168).

BS2

High AC in GnomAd4 at 9 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK4	NM_018216.4 link	c.2101G>A	p.Asp701Asn	missense_variant	Exon 18 of 19	ENST00000378466.9	NP_060686.3	Q9NVE7
PANK4	XM_047424306.1 link	c.1660G>A	p.Asp554Asn	missense_variant	Exon 18 of 19		XP_047280262.1
PANK4	XR_241034.4 link	n.*201G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PANK4	ENST00000378466.9 link	c.2101G>A	p.Asp701Asn	missense_variant	Exon 18 of 19	1	NM_018216.4	ENSP00000367727.5		Q9NVE7

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000686

AC:

AN:

247850

AF XY:

0.0000817

show subpopulations

Gnomad AFR exome

AF:

0.0000631

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000472

Gnomad NFE exome

AF:

0.0000627

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000713

AC:

104

AN:

1459410

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

725980

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.000134

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86108

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5136

European-Non Finnish (NFE)

AF:

0.0000837

AC:

AN:

1111746

Other (OTH)

AF:

0.0000498

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41546

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.547

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000910

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 10, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2101G>A (p.D701N) alteration is located in exon 18 (coding exon 18) of the PANK4 gene. This alteration results from a G to A substitution at nucleotide position 2101, causing the aspartic acid (D) at amino acid position 701 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.39

T;T

MetaSVM

Benign

-1.1

PhyloP100

7.0

PrimateAI

Uncertain

0.79

REVEL

Benign

0.28

Sift4G

Benign

0.066

T;T

Vest4

0.93

MVP

0.62

MPC

1.6

ClinPred

0.87

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=76/24

polymorphism

(source)

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

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rs535092413

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over