rs2277499

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021728.4(OTX2):c.98-46C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,563,348 control chromosomes in the GnomAD database, including 90,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7790 hom., cov: 31)

Exomes 𝑓: 0.34 ( 82760 hom. )

Consequence

OTX2
NM_021728.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.284

Publications

7 publications found

Variant links:

Genes affected

OTX2 (HGNC:8522): (orthodenticle homeobox 2) This gene encodes a member of the bicoid subfamily of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and plays a role in brain, craniofacial, and sensory organ development. The encoded protein also influences the proliferation and differentiation of dopaminergic neuronal progenitor cells during mitosis. Mutations in this gene cause syndromic microphthalmia 5 (MCOPS5) and combined pituitary hormone deficiency 6 (CPHD6). This gene is also suspected of having an oncogenic role in medulloblastoma. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Pseudogenes of this gene are known to exist on chromosomes two and nine. [provided by RefSeq, Jul 2012]

OTX2 Gene-Disease associations (from GenCC):

syndromic microphthalmia type 5
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
pituitary hormone deficiency, combined, 6
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
combined pituitary hormone deficiencies, genetic form
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated anophthalmia-microphthalmia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
patterned macular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
septooptic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

OTX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 14-56804409-G-T is Benign according to our data. Variant chr14-56804409-G-T is described in ClinVar as Benign. ClinVar VariationId is 1292627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021728.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
OTX2	NM_021728.4	MANE Select	c.98-46C>A	intron	N/A	NP_068374.1	F1T0D1
OTX2	NM_001270525.2		c.98-46C>A	intron	N/A	NP_001257454.1	F1T0D1
OTX2	NM_001270523.2		c.98-70C>A	intron	N/A	NP_001257452.1	P32243-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
OTX2	ENST00000672264.2	MANE Select	c.98-46C>A	intron	N/A	ENSP00000500115.1	P32243-2
OTX2	ENST00000554845.2	TSL:1	c.98-46C>A	intron	N/A	ENSP00000451357.2	P32243-2
OTX2	ENST00000339475.10	TSL:1	c.98-70C>A	intron	N/A	ENSP00000343819.5	P32243-1

Frequencies

GnomAD3 genomes

AF:

0.312

AC:

47330

AN:

151730

Hom.:

7783

Cov.:

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.408

Gnomad ASJ

AF:

0.391

Gnomad EAS

AF:

0.210

Gnomad SAS

AF:

0.337

Gnomad FIN

AF:

0.343

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.347

Gnomad OTH

AF:

0.324

GnomAD2 exomes

AF:

0.347

AC:

74531

AN:

214732

AF XY:

0.348

show subpopulations

Gnomad AFR exome

AF:

0.210

Gnomad AMR exome

AF:

0.438

Gnomad ASJ exome

AF:

0.385

Gnomad EAS exome

AF:

0.215

Gnomad FIN exome

AF:

0.346

Gnomad NFE exome

AF:

0.356

Gnomad OTH exome

AF:

0.360

GnomAD4 exome

AF:

0.341

AC:

481018

AN:

1411498

Hom.:

82760

Cov.:

AF XY:

0.341

AC XY:

238246

AN XY:

698570

show subpopulations

African (AFR)

AF:

0.207

AC:

6731

AN:

32444

American (AMR)

AF:

0.435

AC:

18432

AN:

42326

Ashkenazi Jewish (ASJ)

AF:

0.390

AC:

9344

AN:

23984

East Asian (EAS)

AF:

0.192

AC:

7541

AN:

39208

South Asian (SAS)

AF:

0.339

AC:

27349

AN:

80708

European-Finnish (FIN)

AF:

0.332

AC:

16457

AN:

49556

Middle Eastern (MID)

AF:

0.352

AC:

1575

AN:

4478

European-Non Finnish (NFE)

AF:

0.346

AC:

373850

AN:

1080514

Other (OTH)

AF:

0.339

AC:

19739

AN:

58280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

16222

32444

48665

64887

81109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12028

24056

36084

48112

60140

<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:

0.312

AC:

47346

AN:

151850

Hom.:

7790

Cov.:

AF XY:

0.314

AC XY:

23326

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.214

AC:

8844

AN:

41414

American (AMR)

AF:

0.408

AC:

6227

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.391

AC:

1358

AN:

3470

East Asian (EAS)

AF:

0.210

AC:

1084

AN:

5154

South Asian (SAS)

AF:

0.336

AC:

1618

AN:

4816

European-Finnish (FIN)

AF:

0.343

AC:

3614

AN:

10540

Middle Eastern (MID)

AF:

0.313

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.347

AC:

23565

AN:

67900

Other (OTH)

AF:

0.325

AC:

685

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1557

3114

4671

6228

7785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.330

Hom.:

1661

Bravo

AF:

0.315

Asia WGS

AF:

0.296

AC:

1029

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.3

(source)

DANN

Benign

0.78

PhyloP100

-0.28

Mutation Taster

=100/0

polymorphism (auto)

(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

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