dbSNP rs398123693: SOX2:p.Asn24ArgfsTer65 (chr3-181712418-GGCGGCGGCGGCAACTCCACC-G) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_003106.4(SOX2):c.70_89delAACTCCACCGCGGCGGCGGC(p.Asn24ArgfsTer65) variant causes a frameshift change. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

SOX2
NM_003106.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.23

Publications

14 publications found

Variant links:

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 links:

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]

SOX2-OT links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 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 91 pathogenic variants in the truncated region.

PP5

Variant 3-181712418-GGCGGCGGCGGCAACTCCACC-G is Pathogenic according to our data. Variant chr3-181712418-GGCGGCGGCGGCAACTCCACC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 94104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SOX2	NM_003106.4	MANE Select	c.70_89delAACTCCACCGCGGCGGCGGC	p.Asn24ArgfsTer65	frameshift	Exon 1 of 1	NP_003097.1
SOX2-OT	NR_004053.3		n.768-2755_768-2736delAACTCCACCGCGGCGGCGGC		intron	N/A
SOX2-OT	NR_075089.1		n.767+12547_767+12566delAACTCCACCGCGGCGGCGGC		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SOX2	ENST00000325404.3	TSL:6 MANE Select	c.70_89delAACTCCACCGCGGCGGCGGC	p.Asn24ArgfsTer65	frameshift	Exon 1 of 1	ENSP00000323588.1
SOX2-OT	ENST00000466034.7	TSL:1	n.349+12547_349+12566delAACTCCACCGCGGCGGCGGC		intron	N/A
SOX2-OT	ENST00000476964.6	TSL:1	n.482-27139_482-27120delAACTCCACCGCGGCGGCGGC		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150922

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

150922

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73682

African (AFR)

AF:

0.00

AC:

AN:

41054

American (AMR)

AF:

0.00

AC:

AN:

15180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5010

South Asian (SAS)

AF:

0.00

AC:

AN:

4780

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

300

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67664

Other (OTH)

AF:

0.00

AC:

AN:

2068

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Anophthalmia/microphthalmia-esophageal atresia syndrome (7)

not provided (3)

Septo-optic dysplasia sequence (1)

SOX2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.2

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over