1-2508964-G-C

Variant names:

• chr1-2508964-G-C
• rs528581753
• NM_018216.4:c.2205C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018216.4(PANK4):​c.2205C>G​(p.His735Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H735H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PANK4 NM_018216.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13671294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PANK4	NM_018216.4	c.2205C>G	p.His735Gln	missense_variant	Exon 19 of 19	ENST00000378466.9	NP_060686.3
PANK4	XM_047424306.1	c.1764C>G	p.His588Gln	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.2205C>G	p.His735Gln	missense_variant	Exon 19 of 19	1	NM_018216.4	ENSP00000367727.5
PANK4	ENST00000435556.8	c.2088C>G	p.His696Gln	missense_variant	Exon 19 of 19	2		ENSP00000421433.3
PANK4	ENST00000505228.5	n.*323C>G		non_coding_transcript_exon_variant	Exon 16 of 16	5		ENSP00000425932.1
PANK4	ENST00000505228.5	n.*323C>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

Alfa AF: 0.0000251 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.4
DANN	Benign	0.94
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T;.
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.014
PrimateAI	Uncertain	0.62	T
REVEL	Benign	0.074
Sift4G	Benign	0.30	T;T
Vest4		0.25
MVP		0.13
MPC		0.97
ClinPred		0.21	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs528581753; hg19: chr1-2440403;