Genetic Variant MPC2:p.Phe42Leu (chr1-167924521-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001143674.4(MPC2):c.126C>G(p.Phe42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,419,758 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.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

MPC2
NM_001143674.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.97

Publications

0 publications found

Variant links:

Genes affected

MPC2 (HGNC:24515): (mitochondrial pyruvate carrier 2) Enables identical protein binding activity. Predicted to be involved in mitochondrial pyruvate transmembrane transport. Predicted to act upstream of or within mitochondrial acetyl-CoA biosynthetic process from pyruvate and positive regulation of insulin secretion involved in cellular response to glucose stimulus. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

MPC2 links:

DCAF6 (HGNC:30002): (DDB1 and CUL4 associated factor 6) The protein encoded by this gene is a ligand-dependent coactivator of nuclear receptors, including nuclear receptor subfamily 3 group C member 1 (NR3C1), glucocorticoid receptor (GR), and androgen receptor (AR). The encoded protein and DNA damage binding protein 2 (DDB2) may act as tumor promoters and tumor suppressors, respectively, by regulating the level of androgen receptor in prostate tissues. In addition, this protein can act with glucocorticoid receptor to promote human papillomavirus gene expression. [provided by RefSeq, Mar 2017]

DCAF6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPC2	NM_001143674.4 link	c.126C>G	p.Phe42Leu	missense_variant	Exon 3 of 6	ENST00000271373.9	NP_001137146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
MPC2	ENST00000271373.9 link	c.126C>G	p.Phe42Leu	missense_variant	Exon 3 of 6	1	NM_001143674.4	ENSP00000271373.4
MPC2	ENST00000367846.8 link	c.126C>G	p.Phe42Leu	missense_variant	Exon 2 of 5	1		ENSP00000356820.4
MPC2	ENST00000458574.1 link	c.126C>G	p.Phe42Leu	missense_variant	Exon 3 of 5	5		ENSP00000392874.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1419758

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30856

American (AMR)

AF:

0.00

AC:

AN:

37216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24830

East Asian (EAS)

AF:

0.00

AC:

AN:

38448

South Asian (SAS)

AF:

0.00

AC:

AN:

79044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52332

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5502

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1093128

Other (OTH)

AF:

0.00

AC:

AN:

58402

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;D;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.0

.;D;D

M_CAP

Benign

0.042

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Benign

-0.85

MutationAssessor

Pathogenic

3.6

H;H;.

PhyloP100

2.0

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.8

D;D;D

REVEL

Uncertain

0.47

Sift

Benign

0.033

D;D;D

Sift4G

Uncertain

0.042

D;D;D

Vest4

0.76

ClinPred

0.99

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.92

Mutation Taster

=36/64

disease causing

(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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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