rs1553862971
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003106.4(SOX2):c.244_245del(p.Leu82ValfsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L81L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
SOX2
NM_003106.4 frameshift
NM_003106.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.97
Genes affected
SOX2 (HGNC:11195): (SRY-box transcription factor 2) This intronless gene encodes a member of the SRY-related HMG-box (SOX) family of transcription factors involved in the regulation of embryonic development and in the determination of cell fate. The product of this gene is required for stem-cell maintenance in the central nervous system, and also regulates gene expression in the stomach. Mutations in this gene have been associated with optic nerve hypoplasia and with syndromic microphthalmia, a severe form of structural eye malformation. This gene lies within an intron of another gene called SOX2 overlapping transcript (SOX2OT). [provided by RefSeq, Jul 2008]
SOX2-OT (HGNC:20209): (SOX2 overlapping transcript) This gene produces alternatively spliced long non-coding RNAs. These RNAs were observed to be upregulated in tumor cells and positively correlated to expression of the SRY-box 2 gene. Overexpression of these transcripts may promote cell proliferation. [provided by RefSeq, Dec 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 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. There are 35 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-181712601-CTT-C is Pathogenic according to our data. Variant chr3-181712601-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 467822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOX2 | NM_003106.4 | c.244_245del | p.Leu82ValfsTer13 | frameshift_variant | 1/1 | ENST00000325404.3 | |
SOX2-OT | NR_075091.1 | n.783-2581_783-2580del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOX2 | ENST00000325404.3 | c.244_245del | p.Leu82ValfsTer13 | frameshift_variant | 1/1 | NM_003106.4 | P1 | ||
SOX2-OT | ENST00000626948.3 | n.837-2581_837-2580del | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Anophthalmia/microphthalmia-esophageal atresia syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 17, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 26, 2017 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to be de novo in individuals affected with severe microphthalmia (PMID: 24804704). It has also been reported in individuals affected with anophthalmia (PMID: 24498598, 25542770). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the SOX2 gene (p.Leu82Valfs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 223 amino acids of the SOX2 protein. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at