chr3-181712498-T-G

Variant names:

• chr3-181712498-T-G
• rs104893806
• NM_003106.4:c.138T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_003106.4(SOX2):​c.138T>G​(p.Asn46Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N46S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX2 NM_003106.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.09
• Publications: 6 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_003106.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 3-181712498-T-G is Pathogenic according to our data. Variant chr3-181712498-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 12822.Status of the report is no_assertion_criteria_provided, 0 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.138T>G	p.Asn46Lys	missense	Exon 1 of 1	NP_003097.1	P48431
	SOX2-OT	NR_004053.3		n.768-2687T>G		intron	N/A
	SOX2-OT	NR_075089.1		n.767+12615T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOX2	ENST00000325404.3	TSL:6 MANE Select	c.138T>G	p.Asn46Lys	missense	Exon 1 of 1	ENSP00000323588.1	P48431
	SOX2-OT	ENST00000466034.7	TSL:1	n.349+12615T>G		intron	N/A
	SOX2-OT	ENST00000476964.6	TSL:1	n.482-27071T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Anophthalmia/microphthalmia-esophageal atresia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Pathogenic	1.0	D
Eigen	Benign	0.18
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		2.1
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.76		Gain of methylation at N46 (P = 0.0118)
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		1.7
Varity_R		0.95
gMVP		0.99
Mutation Taster		=1/99	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: rs104893806; hg19: chr3-181430286;