1-42456599-C-G

Variant names:

• chr1-42456599-C-G
• rs1015893671
• NM_024664.4:c.34C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024664.4(PPCS):​c.34C>G​(p.Gln12Glu) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q12R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPCS NM_024664.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88

Genes affected

PPCS (HGNC:25686): (phosphopantothenoylcysteine synthetase) Biosynthesis of coenzyme A (CoA) from pantothenic acid (vitamin B5) is an essential universal pathway in prokaryotes and eukaryotes. PPCS (EC 6.3.2.5), one of the last enzymes in this pathway, converts phosphopantothenate to phosphopantothenoylcysteine (Daugherty et al., 2002 [PubMed 11923312]).[supplied by OMIM, Mar 2008]

CCDC30 (HGNC:26103): (coiled-coil domain containing 30)

ACMG classification

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=0.035924405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPCS	NM_024664.4	c.34C>G	p.Gln12Glu	missense_variant	Exon 1 of 3	ENST00000372561.4	NP_078940.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPCS	ENST00000372561.4	c.34C>G	p.Gln12Glu	missense_variant	Exon 1 of 3	1	NM_024664.4	ENSP00000361642.3

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

Inborn genetic diseases Uncertain:1

Aug 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34C>G (p.Q12E) alteration is located in exon 1 (coding exon 1) of the PPCS gene. This alteration results from a C to G substitution at nucleotide position 34, causing the glutamine (Q) at amino acid position 12 to be replaced by a glutamic acid (E). 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	Benign	0.065
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	10
DANN	Benign	0.79
DEOGEN2	Benign	0.20	T;T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.0	.;L;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.50	T;T;.
Sift4G	Benign	1.0	T;T;D
Polyphen		0.0	.;B;.
Vest4		0.14
MutPred		0.26		Loss of MoRF binding (P = 0.0828);Loss of MoRF binding (P = 0.0828);Loss of MoRF binding (P = 0.0828);
MVP		0.36
MPC		0.69
ClinPred		0.058	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.088
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs1015893671; hg19: chr1-42922270;