3-181712413-C-CG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003106.4(SOX2):c.59dup(p.Gly21ArgfsTer75) 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 (★★). 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SOX2 NM_003106.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.31

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 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 59 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-181712413-C-CG is Pathogenic according to our data. Variant chr3-181712413-C-CG is described in ClinVar as [Pathogenic]. Clinvar id is 279895.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.59dup	p.Gly21ArgfsTer75	frameshift_variant	1/1	ENST00000325404.3
SOX2-OT	NR_075091.1	n.783-2766dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOX2	ENST00000325404.3	c.59dup	p.Gly21ArgfsTer75	frameshift_variant	1/1		NM_003106.4	P1
SOX2-OT	ENST00000626948.3	n.837-2766dup		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441344 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 715252

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Anophthalmia/microphthalmia-esophageal atresia syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 03, 2021	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2016	The c.59dupG pathogenic variant in the SOX2 gene has been reported previously using alternate nomenclature (c.60insG) in association with bilateral anophthalmia, abnormal brain MRI, hypogonadotropic hypogonadism, and learning difficulties (Kelberman et al., 2006). The c.59dupG variant causes a frameshift starting with Glycine 21, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 75 of the new reading frame, denoted p.Gly21ArgfsX75. This variant is predicted to cause loss of normal protein function through protein truncation; the last 297 amino acids are replaced with 74 incorrect amino acids. Additionally, functional studies have shown that the c.59dupG variant impairs nuclear localization, DNA binding, and transcriptional activation (Kelberman et al., 2006). The c.59dupG variant was not observed in approximately 5800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.59dupG as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs398122803; hg19: chr3-181430201;