dbSNP rs121908281: RAX2:p.Gly137Cys (chr19-3770767-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_001319074.4(RAX2):c.409G>T(p.Gly137Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,376,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

RAX2
NM_001319074.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-3770767-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1241.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.25067502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAX2	NM_001319074.4 link	c.409G>T	p.Gly137Cys	missense_variant	Exon 3 of 3	ENST00000555633.3	NP_001306003.2
RAX2	NM_032753.4 link	c.409G>T	p.Gly137Cys	missense_variant	Exon 3 of 3		NP_116142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAX2	ENST00000555633.3 link	c.409G>T	p.Gly137Cys	missense_variant	Exon 3 of 3	1	NM_001319074.4	ENSP00000450456.3
RAX2	ENST00000555978.5 link	c.409G>T	p.Gly137Cys	missense_variant	Exon 3 of 3	1		ENSP00000450687.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.27e-7

AC:

AN:

1376258

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

678922

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30458

American (AMR)

AF:

0.00

AC:

AN:

35240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24808

East Asian (EAS)

AF:

0.00

AC:

AN:

35044

South Asian (SAS)

AF:

0.00

AC:

AN:

78826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4902

European-Non Finnish (NFE)

AF:

9.30e-7

AC:

AN:

1075594

Other (OTH)

AF:

0.00

AC:

AN:

57442

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.47

.;T

M_CAP

Benign

0.073

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.9

L;L

PhyloP100

1.1

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.14

.;N

REVEL

Uncertain

0.48

Sift

Uncertain

0.0030

.;D

Sift4G

Benign

0.13

T;T

Polyphen

0.90

P;P

Vest4

0.36

MutPred

0.32

Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);

MVP

0.30

MPC

0.33

ClinPred

0.69

GERP RS

2.8

Varity_R

0.12

gMVP

0.46

Mutation Taster

=29/71

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over