Genetic Variant NM_002979.5:c.62T>C (chr1-52927458-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002979.5(SCP2):c.62T>C(p.Met21Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M21R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SCP2
NM_002979.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.91

Publications

0 publications found

Variant links:

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]

SCP2 links:

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]

ECHDC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCP2	NM_002979.5 link	c.62T>C	p.Met21Thr	missense_variant	Exon 1 of 16	ENST00000371514.8	NP_002970.2	P22307-1A0A384NY87Q59HG9B2R761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCP2	ENST00000371514.8 link	c.62T>C	p.Met21Thr	missense_variant	Exon 1 of 16	1	NM_002979.5	ENSP00000360569.3		P22307-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447694

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718254

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33358

American (AMR)

AF:

0.00

AC:

AN:

42488

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25758

East Asian (EAS)

AF:

0.00

AC:

AN:

39252

South Asian (SAS)

AF:

0.00

AC:

AN:

83140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105954

Other (OTH)

AF:

0.00

AC:

AN:

59876

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

D;.;.;.;D

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.84

D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.1

M;M;M;M;.

PhyloP100

2.9

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-4.7

D;D;D;D;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D;D;.

Sift4G

Uncertain

0.015

D;D;D;D;.

Polyphen

0.96

D;.;.;.;.

Vest4

0.63

MutPred

0.58

Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);

MVP

0.96

MPC

0.70

ClinPred

1.0

GERP RS

3.4

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.89

gMVP

0.93

Mutation Taster

=59/41

polymorphism

(source)

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

Publications

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NM_002979.5:c.62T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over