chr6-42966456-TGGAAAGTGCGTG-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_000287.4(PEX6):c.2095-21_2095-10delCACGCACTTTCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,808 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000287.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PEX6 | NM_000287.4 | c.2095-21_2095-10delCACGCACTTTCC | intron_variant | Intron 10 of 16 | ENST00000304611.13 | NP_000278.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PEX6 | ENST00000304611.13 | c.2095-21_2095-10delCACGCACTTTCC | intron_variant | Intron 10 of 16 | 1 | NM_000287.4 | ENSP00000303511.8 | |||
PEX6 | ENST00000244546.4 | c.2115+36_2115+47delCACGCACTTTCC | intron_variant | Intron 10 of 14 | 1 | ENSP00000244546.4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152050Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251444Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135906
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461758Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 727180
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152050Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74274
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
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In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 15542397, 21520333) -
PEX6-related disorder Pathogenic:1
The PEX6 c.2095-21_2095-10del12 variant is predicted to result in an intronic deletion. This variant, also known as IVS10-10to-21delCCTTTCACGCAC, has been reported along with a second PEX6 missense variant in an individual with a peroxisome biogenesis disorder, Zellweger syndrome, and is noted to alter splicing (Table 4, Steinberg et al. 2004. PubMed ID: 15542397). This variant has been reported in a fibroblast cell line with a second PEX6 truncating variant to impact PEX6 protein levels, however phenotypic information of the original patient was not provided (Figure 3, Levesque et al. 2012. PubMed ID: 22894767). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD and has conflicting classifications in ClinVar ranging from uncertain significance to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/286981/). Taken together, this variant is interpreted as pathogenic. -
Heimler syndrome 2 Pathogenic:1
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Peroxisome biogenesis disorder Pathogenic:1
This sequence change falls in intron 10 of the PEX6 gene. It does not directly change the encoded amino acid sequence of the PEX6 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs772869377, gnomAD 0.02%). This variant has been observed in individuals with Zellweger syndrome (PMID: 15542397, 21520333; internal data). ClinVar contains an entry for this variant (Variation ID: 286981). Studies have shown that this variant results in insertion of additional nucleotides, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 21520333; external communication). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at