chr2-27309919-C-G

Variant names:

• chr2-27309919-C-G
• rs746180658
• NM_002437.5:c.524G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002437.5(MPV17):​c.524G>C​(p.Arg175Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,418 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R175Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MPV17 NM_002437.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.335
• Publications: 0 publications found

Genes affected

MPV17 (HGNC:7224): (mitochondrial inner membrane protein MPV17) This gene encodes a mitochondrial inner membrane protein that is implicated in the metabolism of reactive oxygen species. Mutations in this gene have been associated with the hepatocerebral form of mitochondrial DNA depletion syndrome (MDDS). [provided by RefSeq, Jul 2008]

MPV17 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Charcot-Marie-Tooth disease, axonal, type 2EE

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PM1: In a chain Mitochondrial inner membrane protein Mpv17 (size 175) in uniprot entity MPV17_HUMAN there are 23 pathogenic changes around while only 5 benign (82%) in NM_002437.5
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002437.5. 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
	MPV17	NM_002437.5	MANE Select	c.524G>C	p.Arg175Pro	missense	Exon 8 of 8	NP_002428.1	P39210

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPV17	ENST00000380044.6	TSL:1 MANE Select	c.524G>C	p.Arg175Pro	missense	Exon 8 of 8	ENSP00000369383.1	P39210
	MPV17	ENST00000233545.6	TSL:1	c.524G>C	p.Arg175Pro	missense	Exon 7 of 7	ENSP00000233545.2	P39210
	MPV17	ENST00000911060.1		c.674G>C	p.Arg225Pro	missense	Exon 10 of 10	ENSP00000581119.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461418 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727048

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111608

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.34
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.012	D
Polyphen		0.75	P
Vest4		0.28
MutPred		0.53		Loss of MoRF binding (P = 0)
MVP		0.83
MPC		0.99
ClinPred		0.98	D
GERP RS		-4.3
Varity_R		0.32
gMVP		0.62
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs746180658; hg19: chr2-27532787;