chr3-181712749-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5BS1_SupportingBS2

The NM_003106.4(SOX2):c.389G>C(p.Gly130Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000162 in 1,609,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G130E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SOX2
NM_003106.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 6.57

Publications

8 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP5

Variant 3-181712749-G-C is Pathogenic according to our data. Variant chr3-181712749-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12825.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000197 (3/152272) while in subpopulation SAS AF = 0.000622 (3/4826). AF 95% confidence interval is 0.000169. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 23 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.389G>C	p.Gly130Ala	missense	Exon 1 of 1	NP_003097.1	P48431
SOX2-OT	NR_004053.3		n.768-2436G>C		intron	N/A
SOX2-OT	NR_075089.1		n.767+12866G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SOX2	ENST00000325404.3	TSL:6 MANE Select	c.389G>C	p.Gly130Ala	missense	Exon 1 of 1	ENSP00000323588.1	P48431
SOX2-OT	ENST00000466034.7	TSL:1	n.349+12866G>C		intron	N/A
SOX2-OT	ENST00000476964.6	TSL:1	n.482-26820G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000723

AC:

AN:

235092

AF XY:

0.0000779

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1457506

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

724696

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.00

AC:

AN:

44044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25990

East Asian (EAS)

AF:

0.00

AC:

AN:

39532

South Asian (SAS)

AF:

0.000268

AC:

AN:

85956

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109882

Other (OTH)

AF:

0.00

AC:

AN:

60144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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:

0.00

Hom.:

ExAC

AF:

0.0000745

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Anophthalmia/microphthalmia-esophageal atresia syndrome (3)

Optic nerve hypoplasia and abnormalities of the central nervous system (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.052

MetaRNN

Uncertain

0.49

MetaSVM

Uncertain

0.28

MutationAssessor

Uncertain

2.7

PhyloP100

6.6

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.65

Sift

Benign

0.077

Sift4G

Uncertain

0.024

Polyphen

0.42

Vest4

0.77

MutPred

0.30

Gain of glycosylation at Y125 (P = 0.0034)

MVP

0.96

MPC

2.0

ClinPred

0.30

GERP RS

5.4

Varity_R

0.40

gMVP

0.92

Mutation Taster

=5/95

disease causing (ClinVar)

(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