rs35214083

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_182894.3(VSX2):c.299C>A(p.Pro100Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000823 in 1,577,558 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. P100P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0042 ( 12 hom., cov: 33)

Exomes 𝑓: 0.00047 ( 6 hom. )

Consequence

VSX2
NM_182894.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 3.30

Publications

3 publications found

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]

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), PanelApp Australia
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

VSX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006032586).

BP6

Variant 14-74239860-C-A is Benign according to our data. Variant chr14-74239860-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167839.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00416 (634/152306) while in subpopulation AFR AF = 0.0147 (610/41572). AF 95% confidence interval is 0.0137. There are 12 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VSX2	NM_182894.3 link	c.299C>A	p.Pro100Gln	missense_variant	Exon 1 of 5	ENST00000261980.3	NP_878314.1	P58304

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VSX2	ENST00000261980.3 link	c.299C>A	p.Pro100Gln	missense_variant	Exon 1 of 5	1	NM_182894.3	ENSP00000261980.2		P58304

Frequencies

GnomAD3 genomes

AF:

0.00413

AC:

628

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

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:

0.0000294

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000989

AC:

182

AN:

184000

AF XY:

0.000839

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000395

Gnomad OTH exome

AF:

0.000205

GnomAD4 exome

AF:

0.000467

AC:

665

AN:

1425252

Hom.:

Cov.:

AF XY:

0.000415

AC XY:

293

AN XY:

705448

show subpopulations

African (AFR)

AF:

0.0161

AC:

531

AN:

32980

American (AMR)

AF:

0.000868

AC:

AN:

39176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25364

East Asian (EAS)

AF:

0.00

AC:

AN:

38282

South Asian (SAS)

AF:

0.000184

AC:

AN:

81318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49258

Middle Eastern (MID)

AF:

0.000412

AC:

AN:

4858

European-Non Finnish (NFE)

AF:

0.00000639

AC:

AN:

1094994

Other (OTH)

AF:

0.00129

AC:

AN:

59022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

128

170

213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00416

AC:

634

AN:

152306

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0147

AC:

610

AN:

41572

American (AMR)

AF:

0.00131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68008

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00148

Hom.:

Bravo

AF:

0.00476

ESP6500AA

AF:

0.00618

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000843

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Isolated microphthalmia 2

Benign:2

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Microphthalmia, isolated, with coloboma 3

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Apr 24, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microphthalmia

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 30, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0060

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.4

PhyloP100

3.3

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.35

Sift

Benign

0.076

Sift4G

Benign

0.30

Polyphen

0.85

Vest4

0.31

MVP

0.82

MPC

0.50

ClinPred

0.012

GERP RS

4.8

PromoterAI

0.0077

Neutral

(source)

Varity_R

0.19

gMVP

0.42

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over