rs587779779

Variant names:

• chr19-7631476-C-T
• rs587779779
• NM_001171155.2:c.142C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_001171155.2(PET100):​c.142C>T​(p.Gln48*) 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 (★★). ClinVar reports functional evidence for this variant: "SCV001468551: Well-established functional studies show a deleterious effect (PS3 downgraded to moderate)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PET100 NM_001171155.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.29
• Publications: 3 publications found

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]

ENSG00000268400 (HGNC:):

STXBP2 (HGNC:11445): (syntaxin binding protein 2) This gene encodes a member of the STXBP/unc-18/SEC1 family. The encoded protein is involved in intracellular trafficking, control of SNARE (soluble NSF attachment protein receptor) complex assembly, and the release of cytotoxic granules by natural killer cells. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2013]

PCP2 (HGNC:30209): (Purkinje cell protein 2) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of catalytic activity. Predicted to act upstream of or within rhodopsin mediated signaling pathway. Predicted to be located in neuronal cell body. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.36 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001468551: Well-established functional studies show a deleterious effect (PS3 downgraded to moderate).; SCV004038304: The variant results in <10% complex IV activity in homozygous patient muscle tissue and fibroblasts (e.g., Olahova_2015). PMID: 25293719
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 128250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001171155.2. 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
	PET100	NM_001171155.2	MANE Select	c.142C>T	p.Gln48*	stop_gained	Exon 4 of 4	NP_001164626.1	P0DJ07
	STXBP2	NM_001414484.1		c.-60+630C>T		intron	N/A	NP_001401413.1
	PET100	NR_033242.2		n.273C>T		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PET100	ENST00000594797.6	TSL:1 MANE Select	c.142C>T	p.Gln48*	stop_gained	Exon 4 of 4	ENSP00000470539.1	P0DJ07
	ENSG00000268400	ENST00000698368.1		n.114+817C>T		intron	N/A	ENSP00000513686.1	A0A8V8TM65
	PET100	ENST00000923271.1		c.181C>T	p.Gln61*	stop_gained	Exon 4 of 4	ENSP00000593330.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000725 AC: 1 AN: 137842 AF XY: 0.0000135

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 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

African (AFR) AF: 0.00 AC: 0 AN: 31568

American (AMR) AF: 0.00 AC: 0 AN: 35640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25148

East Asian (EAS) AF: 0.00 AC: 0 AN: 35686

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5460

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078544

Other (OTH) AF: 0.00 AC: 0 AN: 57838

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Mitochondrial complex IV deficiency, nuclear type 12 (2)
1	-	-	Congenital lactic acidosis;C5435656:Mitochondrial complex IV deficiency, nuclear type 1 (1)
1	-	-	Mitochondrial complex IV deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=8/192	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587779779; hg19: chr19-7696362;