chr3-181713194-C-T

Position:

• chr3-181713194-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003106.4(SOX2):​c.834C>T​(p.Leu278Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,613,164 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: SOX2 NM_003106.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.871

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:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 3-181713194-C-T is Benign according to our data. Variant chr3-181713194-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 94105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-181713194-C-T is described in Lovd as [Benign]. Variant chr3-181713194-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.871 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00177 (269/152328) while in subpopulation NFE AF= 0.00272 (185/68030). AF 95% confidence interval is 0.0024. There are 0 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 269 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOX2	NM_003106.4	c.834C>T	p.Leu278Leu	synonymous_variant	1/1	ENST00000325404.3	NP_003097.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOX2	ENST00000325404.3	c.834C>T	p.Leu278Leu	synonymous_variant	1/1	6	NM_003106.4	ENSP00000323588.1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00166 AC: 407 AN: 245292 Hom.: 2 AF XY: 0.00160 AC XY: 215 AN XY: 134022

Gnomad AFR exome AF: 0.000266

Gnomad AMR exome AF: 0.000407

Gnomad ASJ exome AF: 0.00394

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.00250

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00177 AC: 2583 AN: 1460836 Hom.: 4 Cov.: 33 AF XY: 0.00174 AC XY: 1265 AN XY: 726746

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00513

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.00156

Gnomad4 NFE exome AF: 0.00189

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74488

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00272

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00239 Hom.: 0

Bravo AF: 0.00147

EpiCase AF: 0.00196

EpiControl AF: 0.00154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SOX2: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Anophthalmia/microphthalmia-esophageal atresia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.8
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144530684; hg19: chr3-181430982; COSMIC: COSV100327310; COSMIC: COSV100327310;