chr2-27311908-A-AG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_002437.5(MPV17):c.451dupC(p.Leu151ProfsTer39) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000889 in 1,461,548 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

MPV17
NM_002437.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 5.36

Publications

11 publications found

Variant links:

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)

MPV17 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.

PP5

Variant 2-27311908-A-AG is Pathogenic according to our data. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-27311908-A-AG is described in CliVar as Pathogenic. Clinvar id is 38356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPV17	NM_002437.5 link	c.451dupC	p.Leu151ProfsTer39	frameshift_variant	Exon 7 of 8	ENST00000380044.6	NP_002428.1	P39210A0A0S2Z3Z9
MPV17	XM_005264326.5 link	c.451dupC	p.Leu151ProfsTer39	frameshift_variant	Exon 7 of 8		XP_005264383.1	P39210A0A0S2Z3Z9
MPV17	XM_017004151.2 link	c.403dupC	p.Leu135ProfsTer39	frameshift_variant	Exon 7 of 8		XP_016859640.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPV17	ENST00000380044.6 link	c.451dupC	p.Leu151ProfsTer39	frameshift_variant	Exon 7 of 8	1	NM_002437.5	ENSP00000369383.1		P39210

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461548

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.000327

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111960

Other (OTH)

AF:

0.00

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type);C5193076:Charcot-Marie-Tooth disease, axonal, type 2EE

Pathogenic:1

Feb 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial DNA depletion syndrome 15 (hepatocerebral type)

Pathogenic:1

Jul 21, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Dec 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change results in a frameshift in the MPV17 gene (p.Leu151Profs*39). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the MPV17 protein and extend the protein by 12 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with mitochondrial DNA depletion syndrome (PMID: 27536553, 29282788). ClinVar contains an entry for this variant (Variation ID: 38356). For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease, axonal, type 2EE

Pathogenic:1

Jan 27, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

Uncertain:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.4

Mutation Taster

=0/200

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over