NM_002979.5:c.14C>T

Variant names:

• chr1-52927410-C-T
• rs1652528472
• NM_002979.5:c.14C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002979.5(SCP2):​c.14C>T​(p.Pro5Leu) 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. 16/22 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. P5A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCP2 NM_002979.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.04
• Publications: 0 publications found

Genes affected

SCP2 (HGNC:10606): (sterol carrier protein 2) This gene encodes two proteins: sterol carrier protein X (SCPx) and sterol carrier protein 2 (SCP2), as a result of transcription initiation from 2 independently regulated promoters. The transcript initiated from the proximal promoter encodes the longer SCPx protein, and the transcript initiated from the distal promoter encodes the shorter SCP2 protein, with the 2 proteins sharing a common C-terminus. Evidence suggests that the SCPx protein is a peroxisome-associated thiolase that is involved in the oxidation of branched chain fatty acids, while the SCP2 protein is thought to be an intracellular lipid transfer protein. This gene is highly expressed in organs involved in lipid metabolism, and may play a role in Zellweger syndrome, in which cells are deficient in peroxisomes and have impaired bile acid synthesis. Alternative splicing of this gene produces multiple transcript variants, some encoding different isoforms.[provided by RefSeq, Aug 2010]

ECHDC2 (HGNC:23408): (enoyl-CoA hydratase domain containing 2) Predicted to enable enoyl-CoA hydratase activity. Predicted to be involved in fatty acid beta-oxidation. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06568292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCP2	NM_002979.5	c.14C>T	p.Pro5Leu	missense_variant	Exon 1 of 16	ENST00000371514.8	NP_002970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCP2	ENST00000371514.8	c.14C>T	p.Pro5Leu	missense_variant	Exon 1 of 16	1	NM_002979.5	ENSP00000360569.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1445512 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 717064

African (AFR) AF: 0.00 AC: 0 AN: 33314

American (AMR) AF: 0.00 AC: 0 AN: 42054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25706

East Asian (EAS) AF: 0.00 AC: 0 AN: 39112

South Asian (SAS) AF: 0.00 AC: 0 AN: 82858

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5418

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105338

Other (OTH) AF: 0.00 AC: 0 AN: 59796

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the SCP2 protein (p.Pro5Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCP2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.0060
DANN	Benign	0.83
DEOGEN2	Benign	0.18	T;.;.;.;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.54	T;T;T;T;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.066	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.0	N;N;N;N;.
PhyloP100		-3.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.26	N;N;N;N;.
REVEL	Benign	0.089
Sift	Benign	0.19	T;T;T;T;.
Sift4G	Benign	0.18	T;T;T;D;.
Polyphen		0.0	B;.;.;.;.
Vest4		0.065
MutPred		0.32		Loss of glycosylation at P5 (P = 0.0072);Loss of glycosylation at P5 (P = 0.0072);Loss of glycosylation at P5 (P = 0.0072);Loss of glycosylation at P5 (P = 0.0072);Loss of glycosylation at P5 (P = 0.0072);
MVP		0.44
MPC		0.39
ClinPred		0.081	T
GERP RS		-6.4
PromoterAI		0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.021
gMVP		0.51
Mutation Taster		=99/1	polymorphism

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

dbSNP: rs1652528472; hg19: chr1-53393082;