rs2277499

Variant names:

• chr14-56804409-G-T
• rs2277499
• NM_021728.4:c.98-46C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.284
• Publications: 7 publications found

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: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Orphanet
• pituitary hormone deficiency, combined, 6

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTX2	NM_021728.4	c.98-46C>A		intron_variant	Intron 3 of 4	ENST00000672264.2	NP_068374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTX2	ENST00000672264.2	c.98-46C>A		intron_variant	Intron 3 of 4		NM_021728.4	ENSP00000500115.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47330 AN: 151730 Hom.: 7783 Cov.: 31

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

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.: 28 AF XY: 0.341 AC XY: 238246 AN XY: 698570

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

GnomAD4 genome AF: 0.312 AC: 47346 AN: 151850 Hom.: 7790 Cov.: 31 AF XY: 0.314 AC XY: 23326 AN XY: 74238

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: 92 AN: 294

European-Non Finnish (NFE) AF: 0.347 AC: 23565 AN: 67900

Other (OTH) AF: 0.325 AC: 685 AN: 2106

Alfa AF: 0.330 Hom.: 1661

Bravo AF: 0.315

Asia WGS AF: 0.296 AC: 1029 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.3
DANN	Benign	0.78
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2277499; hg19: chr14-57271127; COSMIC: COSV59767049;