1-167924508-T-C

Position:

• chr1-167924508-T-C

Variant summary

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

The NM_001143674.4(MPC2):​c.139A>G​(p.Ile47Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000818 in 1,589,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: MPC2 NM_001143674.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.144

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]

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]

MPC2 (HGNC:):

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=0.040321738).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPC2	NM_001143674.4	c.139A>G	p.Ile47Val	missense_variant	3/6	ENST00000271373.9	NP_001137146.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPC2	ENST00000271373.9	c.139A>G	p.Ile47Val	missense_variant	3/6	1	NM_001143674.4	ENSP00000271373.4
MPC2	ENST00000367846.8	c.139A>G	p.Ile47Val	missense_variant	2/5	1		ENSP00000356820.4
MPC2	ENST00000458574.1	c.139A>G	p.Ile47Val	missense_variant	3/5	5		ENSP00000392874.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151764 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.0000134 AC: 3 AN: 224558 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 121908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000773

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000963

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000556 AC: 8 AN: 1437658 Hom.: 0 Cov.: 28 AF XY: 0.00000560 AC XY: 4 AN XY: 714672

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000251

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000245

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000454

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151764 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74128

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000480

Bravo AF: 0.0000227

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2024

The c.139A>G (p.I47V) alteration is located in exon 3 (coding exon 2) of the MPC2 gene. This alteration results from a A to G substitution at nucleotide position 139, causing the isoleucine (I) at amino acid position 47 to be replaced by a valine (V). 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	0.053
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.7
DANN	Benign	0.83
DEOGEN2	Benign	0.14	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.040	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.39	N;N;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.23	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.83	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.13
MutPred		0.46		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.19
MPC		0.38
ClinPred		0.019	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.58

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

LitVar

Other links and lift over

dbSNP: rs748372294; hg19: chr1-167893746;