chr14-74239619-AG-A

Position:

• chr14-74239619-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_182894.3(VSX2):​c.59del​(p.Ser20IlefsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VSX2 NM_182894.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.63

Genes affected

VSX2 (HGNC:1975): (visual system homeobox 2) This gene encodes a homeobox protein originally described as a retina-specific transcription factor. Mutations in this gene are associated with microphthalmia, cataracts and iris abnormalities. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-74239619-AG-A is Pathogenic according to our data. Variant chr14-74239619-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 1453132.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VSX2	NM_182894.3	c.59del	p.Ser20IlefsTer21	frameshift_variant	1/5	ENST00000261980.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VSX2	ENST00000261980.3	c.59del	p.Ser20IlefsTer21	frameshift_variant	1/5	1	NM_182894.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Isolated microphthalmia 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 25, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with VSX2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser20Ilefs*21) in the VSX2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VSX2 are known to be pathogenic (PMID: 20414678). -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-74706322;