Variant chr3-181712413-CG-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_003106.4(SOX2):c.59del(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). Synonymous variant affecting the same amino acid position (i.e. S18S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SOX2
NM_003106.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.31

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 made for transcript

Verdict is Pathogenic. Variant got 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 61 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 id is 986777.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOX2	NM_003106.4 linkuse as main transcript	c.59del	p.Gly20AlafsTer26	frameshift_variant	1/1	ENST00000325404.3
SOX2-OT	NR_075091.1 linkuse as main transcript	n.783-2766del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX2	ENST00000325404.3 linkuse as main transcript	c.59del	p.Gly20AlafsTer26	frameshift_variant	1/1		NM_003106.4	P1
SOX2-OT	ENST00000626948.3 linkuse as main transcript	n.837-2766del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.94e-7

AC:

AN:

1441354

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715260

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.07e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Anophthalmia/microphthalmia-esophageal atresia syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Anophthalmia/Microphthalmia Research Registry, Einstein Medical Center Philadelphia

Patient has symptoms similar to SOX2 related disease and is suspected to be pathogenic -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over