1-2510686-C-G

Variant names:

• chr1-2510686-C-G
• NM_018216.4:c.1930G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018216.4(PANK4):​c.1930G>C​(p.Gly644Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PANK4 NM_018216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.51
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK4	NM_018216.4	c.1930G>C	p.Gly644Arg	missense_variant	Exon 16 of 19	ENST00000378466.9	NP_060686.3
PANK4	XM_047424306.1	c.1489G>C	p.Gly497Arg	missense_variant	Exon 16 of 19		XP_047280262.1
PANK4	XR_241034.4	n.1905G>C		non_coding_transcript_exon_variant	Exon 16 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PANK4	ENST00000378466.9	c.1930G>C	p.Gly644Arg	missense_variant	Exon 16 of 19	1	NM_018216.4	ENSP00000367727.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1930G>C (p.G644R) alteration is located in exon 16 (coding exon 16) of the PANK4 gene. This alteration results from a G to C substitution at nucleotide position 1930, causing the glycine (G) at amino acid position 644 to be replaced by an arginine (R). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;.
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.96	T
PhyloP100		5.5
PrimateAI	Pathogenic	0.82	D
REVEL	Uncertain	0.50
Sift4G	Uncertain	0.0040	D;D
Vest4		0.76
MVP		0.24
MPC		1.7
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=14/86	disease causing

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

hg19: chr1-2442125;