Genetic Variant SOX2:c.-31C>T (chr3-181712330-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_003106.4(SOX2):c.-31C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00468 in 1,341,842 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0045 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 21 hom. )

Consequence

SOX2
NM_003106.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.417

Publications

1 publications found

Variant links:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BP6

Variant 3-181712330-C-T is Benign according to our data. Variant chr3-181712330-C-T is described in ClinVar as Benign. ClinVar VariationId is 378636.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00454 (689/151672) while in subpopulation NFE AF = 0.00535 (363/67790). AF 95% confidence interval is 0.0049. There are 2 homozygotes in GnomAd4. There are 300 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 689 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	Effect	Exon Rank	Protein	UniProt
SOX2	NM_003106.4	MANE Select	c.-31C>T	5_prime_UTR	Exon 1 of 1	NP_003097.1	P48431
SOX2-OT	NR_004053.3		n.768-2855C>T	intron	N/A
SOX2-OT	NR_075089.1		n.767+12447C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SOX2	ENST00000325404.3	TSL:6 MANE Select	c.-31C>T	5_prime_UTR	Exon 1 of 1	ENSP00000323588.1	P48431
SOX2-OT	ENST00000466034.7	TSL:1	n.349+12447C>T	intron	N/A
SOX2-OT	ENST00000476964.6	TSL:1	n.482-27239C>T	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00449

AC:

680

AN:

151562

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00385

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00407

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00152

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00537

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00363

AC:

AN:

8268

AF XY:

0.00361

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00704

Gnomad ASJ exome

AF:

0.0250

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00678

Gnomad OTH exome

AF:

0.00758

GnomAD4 exome

AF:

0.00470

AC:

5592

AN:

1190170

Hom.:

Cov.:

AF XY:

0.00467

AC XY:

2677

AN XY:

573066

show subpopulations

African (AFR)

AF:

0.00361

AC:

AN:

23280

American (AMR)

AF:

0.00393

AC:

AN:

9404

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

235

AN:

15990

East Asian (EAS)

AF:

0.0000361

AC:

AN:

27708

South Asian (SAS)

AF:

0.00123

AC:

AN:

40586

European-Finnish (FIN)

AF:

0.00204

AC:

AN:

35764

Middle Eastern (MID)

AF:

0.00446

AC:

AN:

3362

European-Non Finnish (NFE)

AF:

0.00492

AC:

4846

AN:

985370

Other (OTH)

AF:

0.00515

AC:

251

AN:

48706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

271

542

814

1085

1356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

212

424

636

848

1060

<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:

0.00454

AC:

689

AN:

151672

Hom.:

Cov.:

AF XY:

0.00405

AC XY:

300

AN XY:

74128

show subpopulations

African (AFR)

AF:

0.00408

AC:

169

AN:

41458

American (AMR)

AF:

0.00406

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5052

South Asian (SAS)

AF:

0.00166

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

10520

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00535

AC:

363

AN:

67790

Other (OTH)

AF:

0.00522

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

122

162

203

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:

0.00434

Hom.:

Bravo

AF:

0.00437

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

0.42

PromoterAI

-0.057

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(source)

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

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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