19-3770916-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BS1_Supporting

The NM_001319074.4(RAX2):c.260G>A(p.Arg87Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,557,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R87W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

RAX2
NM_001319074.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 3.53

Publications

5 publications found

Variant links:

Genes affected

RAX2 (HGNC:18286): (retina and anterior neural fold homeobox 2) This gene encodes a homeodomain-containing protein that plays a role in eye development. Mutation of this gene causes age-related macular degeneration type 6, an eye disorder resulting in accumulations of protein and lipid beneath the retinal pigment epithelium and within the Bruch's membrane. Defects in this gene can also cause cone-rod dystrophy type 11, a disease characterized by the initial degeneration of cone photoreceptor cells and resulting in loss of color vision and visual acuity, followed by the degeneration of rod photoreceptor cells, which progresses to night blindness and the loss of peripheral vision. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

RAX2 Gene-Disease associations (from GenCC):

retinitis pigmentosa
Inheritance: AR Classification: DEFINITIVE, MODERATE Submitted by: G2P, Franklin by Genoox
cone-rod dystrophy 11
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 95
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RAX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32189253).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00019 (29/152304) while in subpopulation SAS AF = 0.000415 (2/4824). AF 95% confidence interval is 0.00023. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAX2	NM_001319074.4 link	c.260G>A	p.Arg87Gln	missense_variant	Exon 3 of 3	ENST00000555633.3	NP_001306003.2	Q96IS3
RAX2	NM_032753.4 link	c.260G>A	p.Arg87Gln	missense_variant	Exon 3 of 3		NP_116142.1	Q96IS3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAX2	ENST00000555633.3 link	c.260G>A	p.Arg87Gln	missense_variant	Exon 3 of 3	1	NM_001319074.4	ENSP00000450456.3		Q96IS3
RAX2	ENST00000555978.5 link	c.260G>A	p.Arg87Gln	missense_variant	Exon 3 of 3	1		ENSP00000450687.2		Q96IS3

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000118

AC:

AN:

160832

AF XY:

0.000146

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000373

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000223

Gnomad OTH exome

AF:

0.000431

GnomAD4 exome

AF:

0.000221

AC:

310

AN:

1405102

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

151

AN XY:

695610

show subpopulations

African (AFR)

AF:

0.0000613

AC:

AN:

32644

American (AMR)

AF:

0.0000264

AC:

AN:

37948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25418

East Asian (EAS)

AF:

0.0000265

AC:

AN:

37764

South Asian (SAS)

AF:

0.0000492

AC:

AN:

81320

European-Finnish (FIN)

AF:

0.0000288

AC:

AN:

34680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5486

European-Non Finnish (NFE)

AF:

0.000269

AC:

294

AN:

1091028

Other (OTH)

AF:

0.000119

AC:

AN:

58814

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000190

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68012

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000187

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000281

AC:

ExAC

AF:

0.0000711

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Age related macular degeneration 6

Pathogenic:1Uncertain:1

Aug 20, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

May 15, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 87 of the RAX2 protein (p.Arg87Gln). This variant is present in population databases (rs121908280, gnomAD 0.02%). This missense change has been observed in individual(s) with age-related macular degeneration (PMID: 15028672). ClinVar contains an entry for this variant (Variation ID: 1240). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RAX2 function (PMID: 15028672). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

0.097

Eigen_PC

Benign

-0.00063

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.92

.;D

M_CAP

Pathogenic

0.42

MetaRNN

Benign

0.32

T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

0.90

L;L

PhyloP100

3.5

PrimateAI

Uncertain

0.67

REVEL

Uncertain

0.57

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.98

D;D

Vest4

0.27

MVP

0.54

MPC

0.30

ClinPred

0.16

GERP RS

0.80

Varity_R

0.15

gMVP

0.57

Mutation Taster

=10/90

disease causing

(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