rs146343535
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_004279.3(PMPCB):āc.601G>Cā(p.Ala201Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004279.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMPCB | NM_004279.3 | c.601G>C | p.Ala201Pro | missense_variant | 5/13 | ENST00000249269.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMPCB | ENST00000249269.9 | c.601G>C | p.Ala201Pro | missense_variant | 5/13 | 1 | NM_004279.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152182Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251368Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135850
GnomAD4 exome AF: 0.0000807 AC: 118AN: 1461700Hom.: 0 Cov.: 31 AF XY: 0.0000770 AC XY: 56AN XY: 727160
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74342
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 06, 2021 | The c.601G>C (p.A201P) alteration is located in coding exon 5 of the PMPCB gene. This alteration results from a G to C substitution at nucleotide position 601, causing the alanine (A) at amino acid position 201 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of <0.01% (9/282768) total alleles studied. This alteration has been reported, in trans with c.523C>T (p.R175C), in two affected individuals with developmental regression, seizures, abnormal brain MRI, elevated serum lactate, and inability to walk (Vögtle, 2018). This amino acid position is highly conserved in available vertebrate species. Functional analysis of the yeast Mas1 homologous p.A201P alteration showed a defect in mitochondrial precursor processing under heat shock. Additionally, muscle biopsy from one affected individual heterozygous for this variant in trans with c.523C>T (p.R175C) showed severely decreased complex II activity, as well as deficient activity of both the cytosolic and mitochondrial aconitase enzymes (Vögtle, 2018). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Multiple mitochondrial dysfunctions syndrome 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 29, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 16, 2022 | PM2, PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at