2-27312510-C-G

Variant names:

• chr2-27312510-C-G
• rs121909724
• NM_002437.5:c.359G>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.359G>C​(p.Trp120Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. W120C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPV17 NM_002437.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.99
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), 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 Protein Mpv17 (size 175) in uniprot entity MPV17_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_002437.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPV17	NM_002437.5	c.359G>C	p.Trp120Ser	missense_variant	Exon 5 of 8	ENST00000380044.6	NP_002428.1
MPV17	XM_005264326.5	c.359G>C	p.Trp120Ser	missense_variant	Exon 5 of 8		XP_005264383.1
MPV17	XM_017004151.2	c.311G>C	p.Trp104Ser	missense_variant	Exon 5 of 8		XP_016859640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPV17	ENST00000380044.6	c.359G>C	p.Trp120Ser	missense_variant	Exon 5 of 8	1	NM_002437.5	ENSP00000369383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	T;.;T;T;T;T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	.;D;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.1	L;.;L;.;.;.;.
PhyloP100		4.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.25	T;T;T;T;T;T;T
Sift4G	Benign	0.47	T;D;T;T;T;T;.
Polyphen		0.40	B;P;B;.;.;.;.
Vest4		0.66
MutPred		0.56		Gain of disorder (P = 0);Gain of disorder (P = 0);Gain of disorder (P = 0);.;.;Gain of disorder (P = 0);.;
MVP		0.79
MPC		1.1
ClinPred		0.87	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.53
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121909724; hg19: chr2-27535377;