1-167935811-C-T

Variant names:

• chr1-167935811-C-T
• rs761366753
• NM_001143674.4:c.31G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001143674.4(MPC2):​c.31G>A​(p.Ala11Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,403,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. A11P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MPC2 NM_001143674.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.42
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34968227).

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.31G>A	p.Ala11Thr	missense	Exon 2 of 6	NP_001137146.1	O95563
	MPC2	NM_015415.3		c.31G>A	p.Ala11Thr	missense	Exon 2 of 6	NP_056230.1	O95563
	MPC2	NR_026550.3		n.186G>A		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPC2	ENST00000271373.9	TSL:1 MANE Select	c.31G>A	p.Ala11Thr	missense	Exon 2 of 6	ENSP00000271373.4	O95563
	MPC2	ENST00000367846.8	TSL:1	c.31G>A	p.Ala11Thr	missense	Exon 1 of 5	ENSP00000356820.4	O95563
	MPC2	ENST00000856458.1		c.31G>A	p.Ala11Thr	missense	Exon 2 of 6	ENSP00000526517.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403762 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 693074

African (AFR) AF: 0.00 AC: 0 AN: 31906

American (AMR) AF: 0.00 AC: 0 AN: 36446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25238

East Asian (EAS) AF: 0.00 AC: 0 AN: 36384

South Asian (SAS) AF: 0.00 AC: 0 AN: 79690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4302

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082358

Other (OTH) AF: 0.00 AC: 0 AN: 58072

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.16
Sift	Benign	0.097	T
Sift4G	Benign	0.20	T
Polyphen		0.88	P
Vest4		0.40
MutPred		0.28		Loss of helix (P = 0.0167)
MVP		0.34
MPC		0.45
ClinPred		0.95	D
GERP RS		5.2
PromoterAI		-0.071	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.69
Mutation Taster		=59/41	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: rs761366753; hg19: chr1-167905049;