dbSNP rs144530684: SOX2:p.Leu278Leu (chr3-181713194-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.871

Publications

3 publications found

Variant links:

COSMIC-nc: COSV100327310

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 links:

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]

SOX2-OT links:

ENSG00000294981 (HGNC:):

ENSG00000294981 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 94105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 269 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SOX2	NM_003106.4	MANE Select	c.834C>T	p.Leu278Leu	synonymous	Exon 1 of 1	NP_003097.1	P48431
SOX2-OT	NR_004053.3		n.768-1991C>T		intron	N/A
SOX2-OT	NR_075089.1		n.767+13311C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SOX2	ENST00000325404.3	TSL:6 MANE Select	c.834C>T	p.Leu278Leu	synonymous	Exon 1 of 1	ENSP00000323588.1	P48431
SOX2-OT	ENST00000466034.7	TSL:1	n.349+13311C>T		intron	N/A
SOX2-OT	ENST00000476964.6	TSL:1	n.482-26375C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

270

AN:

152210

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00166

AC:

407

AN:

245292

AF XY:

0.00160

show subpopulations

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 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.:

Cov.:

AF XY:

0.00174

AC XY:

1265

AN XY:

726746

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000581

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00513

AC:

134

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00125

AC:

108

AN:

86248

European-Finnish (FIN)

AF:

0.00156

AC:

AN:

52442

Middle Eastern (MID)

AF:

0.00329

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00189

AC:

2104

AN:

1111986

Other (OTH)

AF:

0.00171

AC:

103

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

181

362

543

724

905

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00177

AC:

269

AN:

152328

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

130

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41576

American (AMR)

AF:

0.00190

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00104

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00272

AC:

185

AN:

68030

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00239

Hom.:

Bravo

AF:

0.00147

EpiCase

AF:

0.00196

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Anophthalmia/microphthalmia-esophageal atresia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

9.8

(source)

DANN

Benign

0.94

PhyloP100

0.87

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over