rs398123693

chr3-181712418-GGCGGCGGCGGCAACTCCACC-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003106.4(SOX2):c.70_89del(p.Asn24ArgfsTer65) variant causes a frameshift change. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 6.23

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 58 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 id is 94104.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.70_89del	p.Asn24ArgfsTer65	frameshift_variant	1/1	ENST00000325404.3
SOX2-OT	NR_075091.1	n.783-2755_783-2736del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX2	ENST00000325404.3	c.70_89del	p.Asn24ArgfsTer65	frameshift_variant	1/1		NM_003106.4	P1
SOX2-OT	ENST00000626948.3	n.837-2755_837-2736del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150922 Hom.: 0 Cov.: 32 FAILED QC

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: 0 AN: 150922 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73682

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anophthalmia/microphthalmia-esophageal atresia syndrome Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 94104). This variant is also known as c.70del20. This premature translational stop signal has been observed in individual(s) with bilateral anophthalmia or microphthalmia with or without additional features (PMID: 18285410, 24804704, 26250054, 27206652). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn24Argfs*65) in the SOX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 294 amino acid(s) of the SOX2 protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 25, 2021	ACMG classification criteria: PVS1 strong, PS4 very strong, PM2 moderate, PM6 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 22, 2023	PVS1, PS2, PS4, PM2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as pathogenic (PMID: 27206652, 26250054).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2021	Published functional studies demonstrate a loss of protein function (Kelberman et al., 2006; Suzuki et al., 2014); Not observed in large population cohorts (Lek et al., 2016); Frameshift variant in the C-terminus predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24859618, 17522144, 29371155, 24498598, 26250054, 27206652, 16283891, 16932809, 16892407, 24804704, 18285410, 30450772, 30262714, 31005762, 31278258, 31884615, 33144682) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -

SOX2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

The SOX2 c.70_89del20 variant is predicted to result in a frameshift and premature protein termination (p.Asn24Argfs*65). This variant has been reported in multiple unrelated individuals with syndromic microphthalmia, and in at least 2 individuals was reported to have arisen de novo (Zenteno et al. 2005. PubMed ID: 16283891; Suzuki et al. 2014. PubMed ID: 24804704; Chacon-Camacho et al. 2015. PubMed ID: 26250054). In one individual with normal eye size, other findings included facial dysmorphisms, ocular findings (alternating esotropia, inferior oblique overaction and hyperopia), and an enlarging suprasellar lesion (Blackburn et al. 2018. PubMed ID: 30450772). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in SOX2 are expected to be pathogenic and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/94104). This variant is interpreted as pathogenic. -

Septo-optic dysplasia sequence Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Human Developmental Genetics Laboratory, Medical College of Wisconsin

Jun 03, 2022

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398123693; hg19: chr3-181430206;