chr1-2508976-G-C

Variant names:

• chr1-2508976-G-C
• NM_018216.4:c.2193C>G

Variant summary

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

The NM_018216.4(PANK4):​c.2193C>G​(p.His731Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 1.21
• 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.2193C>G	p.His731Gln	missense_variant	Exon 19 of 19	ENST00000378466.9	NP_060686.3
PANK4	XM_047424306.1	c.1752C>G	p.His584Gln	missense_variant	Exon 19 of 19		XP_047280262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PANK4	ENST00000378466.9	c.2193C>G	p.His731Gln	missense_variant	Exon 19 of 19	1	NM_018216.4	ENSP00000367727.5
PANK4	ENST00000435556.8	c.2076C>G	p.His692Gln	missense_variant	Exon 19 of 19	2		ENSP00000421433.3
PANK4	ENST00000505228.5	n.*311C>G		non_coding_transcript_exon_variant	Exon 16 of 16	5		ENSP00000425932.1
PANK4	ENST00000505228.5	n.*311C>G		3_prime_UTR_variant	Exon 16 of 16	5		ENSP00000425932.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2193C>G (p.H731Q) alteration is located in exon 19 (coding exon 19) of the PANK4 gene. This alteration results from a C to G substitution at nucleotide position 2193, causing the histidine (H) at amino acid position 731 to be replaced by a glutamine (Q). 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	0.99
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PrimateAI	Pathogenic	0.84	D
REVEL	Uncertain	0.41
Sift4G	Pathogenic	0.0	D;D
Vest4		0.89
MVP		0.53
MPC		1.6
ClinPred		1.0	D
GERP RS		0.091
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-2440415;