rs587779779

Positions:

• chr19-7631476-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The ENST00000594797.6(PET100):​c.142C>T​(p.Gln48Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,383,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PET100 ENST00000594797.6 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.29

Genes affected

PET100 (HGNC:40038): (PET100 cytochrome c oxidase chaperone) Mitochondrial complex IV, or cytochrome c oxidase, is a large transmembrane protein complex that is part of the respiratory electron transport chain of mitochondria. The small protein encoded by this gene plays a role in the biogenesis of mitochondrial complex IV. This protein localizes to the inner mitochondrial membrane and is exposed to the intermembrane space. Mutations in this gene are associated with mitochondrial complex IV deficiency. This gene has a pseudogene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

STXBP2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-7631476-C-T is Pathogenic according to our data. Variant chr19-7631476-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 128250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7631476-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PET100	NM_001171155.2	c.142C>T	p.Gln48Ter	stop_gained	4/4	ENST00000594797.6	NP_001164626.1
STXBP2	NM_001414484.1	c.-60+630C>T		intron_variant			NP_001401413.1
PET100	NR_033242.2	n.273C>T		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PET100	ENST00000594797.6	c.142C>T	p.Gln48Ter	stop_gained	4/4	1	NM_001171155.2	ENSP00000470539	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000725 AC: 1 AN: 137842 Hom.: 0 AF XY: 0.0000135 AC XY: 1 AN XY: 74274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000441

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1383810 Hom.: 0 Cov.: 32 AF XY: 0.00000293 AC XY: 2 AN XY: 682842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000253

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000327 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex 4 deficiency, nuclear type 12 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 23, 2020	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Dec 04, 2020	This variant is interpreted as Likely pathogenic for Mitochondrial complex IV deficiency, nuclear type 12, autosomal recessive. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants (PM4); Well-established functional studies show a deleterious effect (PS3 downgraded to moderate). -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 07, 2023

Variant summary: PET100 c.142C>T (p.Gln48X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a known mechanisms for disease. While this variant is not expected to result in nonsense mediated decay, it is predicted to disrupt the last 26 amino acids of the protein. The variant allele was found at a frequency of 7.3e-06 in 137842 control chromosomes (i.e., 1 heterozygote; gnomAD v2 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.142C>T has been reported in the literature in at least one homozygous individual affected with Cytochrome-c oxidase deficiency disease (e.g., Olahova_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% complex IV activity in homozygous patient muscle tissue and fibroblasts (e.g., Olahova_2015). The following publication was ascertained in the context of this evaluation (PMID: 25293719). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital lactic acidosis;C5435656:Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wellcome Centre for Mitochondrial Research, Newcastle University

May 12, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.066
FATHMM_MKL	Benign	0.43	N
MutationTaster	Benign	1.0	D
Vest4		0.092
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587779779; hg19: chr19-7696362;