rs121912544
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate
The NM_182894.3(VSX2):c.599G>A(p.Arg200Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R200P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_182894.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VSX2 | NM_182894.3 | c.599G>A | p.Arg200Gln | missense_variant | 4/5 | ENST00000261980.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VSX2 | ENST00000261980.3 | c.599G>A | p.Arg200Gln | missense_variant | 4/5 | 1 | NM_182894.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
Microphthalmia, cataracts, and iris abnormalities Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
Isolated microphthalmia 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 02, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg200 amino acid residue in VSX2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10932181, 17661825). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects VSX2 function (PMID: 10932181, 23028343, 27013732). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14860). This missense change has been observed in individual(s) with microphthalmia (PMID: 10932181). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121912543, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 200 of the VSX2 protein (p.Arg200Gln). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at