14-74259689-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1PM2PM5PP3_ModeratePP5_Moderate

The NM_182894.3(VSX2):​c.667G>C​(p.Gly223Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G223A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

VSX2
NM_182894.3 missense

Scores

16
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.92
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS1
Transcript NM_182894.3 (VSX2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.916
PP5
Variant 14-74259689-G-C is Pathogenic according to our data. Variant chr14-74259689-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2112771.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VSX2NM_182894.3 linkc.667G>C p.Gly223Arg missense_variant Exon 4 of 5 ENST00000261980.3 NP_878314.1 P58304

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VSX2ENST00000261980.3 linkc.667G>C p.Gly223Arg missense_variant Exon 4 of 5 1 NM_182894.3 ENSP00000261980.2 P58304

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Isolated microphthalmia 2 Pathogenic:1
Mar 15, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 223 of the VSX2 protein (p.Gly223Arg). 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. This variant disrupts the p.Gly223 amino acid residue in VSX2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21976963). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). A different variant (c.667G>A) giving rise to the same protein effect has been determined to be pathogenic (PMID: 21976963, 24033328, 30181649). This suggests that this variant is also likely to be causative of disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.80
D
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.92
D
MetaSVM
Uncertain
0.76
D
MutationAssessor
Uncertain
2.2
M
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-7.9
D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
1.0
MutPred
0.64
Gain of MoRF binding (P = 0.0085);
MVP
0.91
MPC
0.91
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.93
gMVP
0.88

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: chr14-74726392; API