3-181712413-CG-CGG

Variant names:

• chr3-181712413-C-CG
• rs398122803
• NM_003106.4:c.59dupG

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_003106.4(SOX2):​c.59dupG​(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 (★★). ClinVar reports functional evidence for this variant: "SCV000329529: Published functional studies demonstrate this variant impairs nuclear localization, DNA binding, and transcriptional activation (PMID:16932809)".

• 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:5
• 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]

ACMG classification

Our verdict: Pathogenic. The variant received 22 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 96 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329529: Published functional studies demonstrate this variant impairs nuclear localization, DNA binding, and transcriptional activation (PMID: 16932809)
• 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 VariationId is 279895.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX2	NM_003106.4	MANE Select	c.59dupG	p.Gly21ArgfsTer75	frameshift	Exon 1 of 1	NP_003097.1	P48431
	SOX2-OT	NR_004053.3		n.768-2766dupG		intron	N/A
	SOX2-OT	NR_075089.1		n.767+12536dupG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX2	ENST00000325404.3	TSL:6 MANE Select	c.59dupG	p.Gly21ArgfsTer75	frameshift	Exon 1 of 1	ENSP00000323588.1	P48431
	SOX2-OT	ENST00000466034.7	TSL:1	n.349+12536dupG		intron	N/A
	SOX2-OT	ENST00000476964.6	TSL:1	n.482-27150dupG		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000143 AC: 3 AN: 209562 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000223

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 32894

American (AMR) AF: 0.00 AC: 0 AN: 41626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 38676

South Asian (SAS) AF: 0.00 AC: 0 AN: 84776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5180

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102008

Other (OTH) AF: 0.00 AC: 0 AN: 59450

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Anophthalmia/microphthalmia-esophageal atresia syndrome (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398122803; hg19: chr3-181430201;