rs147896150

chr14-56802185-C-Gchr14-56802185-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_021728.4(OTX2):c.444G>C(p.Pro148=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,614,062 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P148P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: OTX2 NM_021728.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.65

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=-0.86).
• BP6: Variant 14-56802185-C-G is Benign according to our data. Variant chr14-56802185-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196589.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}. Variant chr14-56802185-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00126 (192/152224) while in subpopulation AFR AF= 0.00428 (178/41542). AF 95% confidence interval is 0.00377. There are 0 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTX2	NM_021728.4	c.444G>C	p.Pro148=	synonymous_variant	5/5	ENST00000672264.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTX2	ENST00000672264.2	c.444G>C	p.Pro148=	synonymous_variant	5/5		NM_021728.4	A1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000382 AC: 96 AN: 251358 Hom.: 1 AF XY: 0.000302 AC XY: 41 AN XY: 135868

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000162 AC: 237 AN: 1461838 Hom.: 1 Cov.: 32 AF XY: 0.000147 AC XY: 107 AN XY: 727204

Gnomad4 AFR exome AF: 0.00421

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74442

Gnomad4 AFR AF: 0.00428

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.0000670 Hom.: 0

Bravo AF: 0.00149

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2014	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Anophthalmia-microphthalmia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.23
Dann	Benign	0.36

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: rs147896150; hg19: chr14-57268903;