rs2277499

chr14-56804409-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -0.284

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 1292627.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-56804409-G-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
OTX2	NM_021728.4	c.98-46C>A		intron_variant		ENST00000672264.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTX2	ENST00000672264.2	c.98-46C>A		intron_variant			NM_021728.4	A1

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

GnomAD3 exomes AF: 0.347 AC: 74531 AN: 214732 Hom.: 12976 AF XY: 0.348 AC XY: 40676 AN XY: 116808

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 SAS exome AF: 0.350

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

Gnomad4 AFR exome AF: 0.207

Gnomad4 AMR exome AF: 0.435

Gnomad4 ASJ exome AF: 0.390

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.332

Gnomad4 NFE exome AF: 0.346

Gnomad4 OTH exome AF: 0.339

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

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.408

Gnomad4 ASJ AF: 0.391

Gnomad4 EAS AF: 0.210

Gnomad4 SAS AF: 0.336

Gnomad4 FIN AF: 0.343

Gnomad4 NFE AF: 0.347

Gnomad4 OTH AF: 0.325

Alfa AF: 0.333 Hom.: 1650

Bravo AF: 0.315

Asia WGS AF: 0.296 AC: 1029 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	3.3
Dann	Benign	0.78

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

LitVar

Other links and lift over

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