rs886041039

Variant names:

• chr19-3770700-AAGCCATCTGCG-A
• rs886041039
• NM_001319074.4:c.465_475delCGCAGATGGCT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_001319074.4(RAX2):​c.465_475delCGCAGATGGCT​(p.Ala156ArgfsTer131) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000723 in 1,383,462 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F155F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RAX2 NM_001319074.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.52
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.162 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 19-3770700-AAGCCATCTGCG-A is Pathogenic according to our data. Variant chr19-3770700-AAGCCATCTGCG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 208124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAX2	NM_001319074.4	c.465_475delCGCAGATGGCT	p.Ala156ArgfsTer131	frameshift_variant	Exon 3 of 3	ENST00000555633.3	NP_001306003.2
RAX2	NM_032753.4	c.465_475delCGCAGATGGCT	p.Ala156ArgfsTer131	frameshift_variant	Exon 3 of 3		NP_116142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAX2	ENST00000555633.3	c.465_475delCGCAGATGGCT	p.Ala156ArgfsTer131	frameshift_variant	Exon 3 of 3	1	NM_001319074.4	ENSP00000450456.3
RAX2	ENST00000555978.5	c.465_475delCGCAGATGGCT	p.Ala156ArgfsTer131	frameshift_variant	Exon 3 of 3	1		ENSP00000450687.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383462 Hom.: 0 AF XY: 0.00000146 AC XY: 1 AN XY: 682770

African (AFR) AF: 0.00 AC: 0 AN: 31500

American (AMR) AF: 0.00 AC: 0 AN: 35660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25114

East Asian (EAS) AF: 0.00 AC: 0 AN: 35688

South Asian (SAS) AF: 0.00 AC: 0 AN: 79200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5318

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078412

Other (OTH) AF: 0.00 AC: 0 AN: 57800

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the RAX2 gene (p.Ala156Argfs*131). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the RAX2 protein and extend the protein by 101 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individuals with autosomal dominant cone–rod dystrophy or retinitis pigmentosa (PMID: 25789692; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208124). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Oct 07, 2020

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation as the last 29 amino acids are replaced with 130 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25789692) -

Cone-rod dystrophy 11 Pathogenic:1

Jun 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Retinal dystrophy Pathogenic:1

Aug 12, 2019

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886041039; hg19: chr19-3770698;