3-181712413-CG-C
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_003106.4(SOX2):c.59delG(p.Gly20AlafsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SOX2
NM_003106.4 frameshift
NM_003106.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.31
Publications
4 publications found
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 was made for transcript
Our verdict: Pathogenic. The variant received 11 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 94 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-181712413-CG-C is Pathogenic according to our data. Variant chr3-181712413-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 986777.Status of the report is no_assertion_criteria_provided, 0 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_003106.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SOX2 | NM_003106.4 | MANE Select | c.59delG | p.Gly20AlafsTer26 | frameshift | Exon 1 of 1 | NP_003097.1 | ||
| SOX2-OT | NR_004053.3 | n.768-2766delG | intron | N/A | |||||
| SOX2-OT | NR_075089.1 | n.767+12536delG | intron | N/A |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SOX2 | ENST00000325404.3 | TSL:6 MANE Select | c.59delG | p.Gly20AlafsTer26 | frameshift | Exon 1 of 1 | ENSP00000323588.1 | ||
| SOX2-OT | ENST00000466034.7 | TSL:1 | n.349+12536delG | intron | N/A | ||||
| SOX2-OT | ENST00000476964.6 | TSL:1 | n.482-27150delG | intron | N/A |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.94e-7 AC: 1AN: 1441354Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1AN XY: 715260 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1441354
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
715260
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
32894
American (AMR)
AF:
AC:
0
AN:
41626
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25754
East Asian (EAS)
AF:
AC:
0
AN:
38676
South Asian (SAS)
AF:
AC:
0
AN:
84776
European-Finnish (FIN)
AF:
AC:
0
AN:
50990
Middle Eastern (MID)
AF:
AC:
0
AN:
5180
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1102008
Other (OTH)
AF:
AC:
0
AN:
59450
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Anophthalmia/microphthalmia-esophageal atresia syndrome Pathogenic:1
Anophthalmia/Microphthalmia Research Registry, Einstein Medical Center Philadelphia
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research
Patient has symptoms similar to SOX2 related disease and is suspected to be pathogenic
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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