1-167924521-G-C

Variant names:

• chr1-167924521-G-C
• rs9618
• NM_001143674.4:c.126C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.97
• Publications: 0 publications found

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]

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143674.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPC2	NM_001143674.4	MANE Select	c.126C>G	p.Phe42Leu	missense	Exon 3 of 6	NP_001137146.1	O95563
	MPC2	NM_015415.3		c.126C>G	p.Phe42Leu	missense	Exon 3 of 6	NP_056230.1	O95563
	MPC2	NR_026550.3		n.281C>G		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPC2	ENST00000271373.9	TSL:1 MANE Select	c.126C>G	p.Phe42Leu	missense	Exon 3 of 6	ENSP00000271373.4	O95563
	MPC2	ENST00000367846.8	TSL:1	c.126C>G	p.Phe42Leu	missense	Exon 2 of 5	ENSP00000356820.4	O95563
	MPC2	ENST00000856458.1		c.126C>G	p.Phe42Leu	missense	Exon 3 of 6	ENSP00000526517.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1419758 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 705482

African (AFR) AF: 0.00 AC: 0 AN: 30856

American (AMR) AF: 0.00 AC: 0 AN: 37216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24830

East Asian (EAS) AF: 0.00 AC: 0 AN: 38448

South Asian (SAS) AF: 0.00 AC: 0 AN: 79044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1093128

Other (OTH) AF: 0.00 AC: 0 AN: 58402

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		2.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.47
Sift	Benign	0.033	D
Sift4G	Uncertain	0.042	D
Polyphen		0.0020	B
Vest4		0.76
MutPred		0.78		Gain of catalytic residue at F42 (P = 0.0381)
MVP		0.22
MPC		0.79
ClinPred		0.99	D
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

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: rs9618; hg19: chr1-167893759;