4-25145129-G-GC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_016955.4(SEPSECS):c.808dupG(p.Ala270GlyfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000713 in 1,613,584 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_016955.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152018Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250496Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135768
GnomAD4 exome AF: 0.0000746 AC: 109AN: 1461566Hom.: 0 Cov.: 32 AF XY: 0.0000770 AC XY: 56AN XY: 727080
GnomAD4 genome AF: 0.0000395 AC: 6AN: 152018Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74242
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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The c.808dupG pathogenic variant in the SEPSECS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Alanine 270, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Ala270GlyfsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.808dupG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.808dupG as a pathogenic variant. -
This sequence change creates a premature translational stop signal (p.Ala270Glyfs*5) in the SEPSECS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SEPSECS are known to be pathogenic (PMID: 25558065, 25590979, 26115735). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SEPSECS-related conditions. ClinVar contains an entry for this variant (Variation ID: 279890). For these reasons, this variant has been classified as Pathogenic. -
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Pontocerebellar hypoplasia type 2D Pathogenic:2
The c.808dupG variant in SEPSECS is a frameshift variant. The variant has been reported in other patient with similar phenotype. The variant was identifed as a compound heterozygote with c.846G>A that was shown by RNAseq to result in exon skipping that leads to a frameshift. -
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Inborn genetic diseases Pathogenic:1
The c.808dupG (p.A270Gfs*5) alteration, located in exon 7 (coding exon 7) of the SEPSECS gene, consists of a duplication of G at position 808, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the GG allele has an overall frequency of <0.01% (5/281872) total alleles studied. The highest observed frequency was <0.01% (4/128848) of European (non-Finnish) alleles. This variant was confirmed in trans with a synonymous SEPSECS variant with a predicted splicing impact in a child with global developmental delay, cerebral atrophy, dyskinesia, hypotonia, myopathic facies, cortical visual impairment, and sleep disturbance (Lee, 2020). Based on the available evidence, this alteration is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at