3-181712380-C-T

Variant names:

• chr3-181712380-C-T
• rs1714834018
• NM_003106.4:c.20C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_003106.4(SOX2):​c.20C>T​(p.Thr7Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000356 in 1,404,628 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SOX2 NM_003106.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.20

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX2	NM_003106.4	c.20C>T	p.Thr7Met	missense_variant	Exon 1 of 1	ENST00000325404.3	NP_003097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX2	ENST00000325404.3	c.20C>T	p.Thr7Met	missense_variant	Exon 1 of 1	6	NM_003106.4	ENSP00000323588.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1404628 Hom.: 0 Cov.: 33 AF XY: 0.00000288 AC XY: 2 AN XY: 694312

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: 0.00000369

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital aniridia Uncertain:1

Apr 17, 2020

Medical Genetics Lab, Policlinico S. Orsola.Malpighi

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is absent in GnomAD and has supportive pathogenic computational verdict, but it is outside the HMG domain, where most pathogenic missense variants in SOX genes are located. It was transmitted by a healthy father. Thus, although SOX variants often show incomplete penetrance and variable clinical expressivity, we classify it as of uncertain significance. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.67	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.15		Gain of glycosylation at Y2 (P = 7e-04);
MVP		0.99
MPC		1.6
ClinPred		0.98	D
GERP RS		3.2
Varity_R		0.42
gMVP		0.83

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: rs1714834018; hg19: chr3-181430168;