14-74245231-C-G

Variant names:

• chr14-74245231-C-G
• NM_182894.3:c.522C>G
• VSX2 p.Asp174Glu

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_182894.3(VSX2):​c.522C>G​(p.Asp174Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D174D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 29)
• Consequence: VSX2 NM_182894.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.819
• Publications: 0 publications found

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]

VSX2 Gene-Disease associations (from GenCC):

• isolated microphthalmia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• microphthalmia, isolated, with coloboma 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• microphthalmia

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• isolated anophthalmia-microphthalmia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• microphthalmia, isolated, with coloboma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182894.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX2	NM_182894.3	MANE Select	c.522C>G	p.Asp174Glu	missense	Exon 3 of 5	NP_878314.1	P58304

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX2	ENST00000261980.3	TSL:1 MANE Select	c.522C>G	p.Asp174Glu	missense	Exon 3 of 5	ENSP00000261980.2	P58304

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		-0.82
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.95
gMVP		0.61
Mutation Taster		=42/58	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr14-74711934;