rs549932754

Variant names:

• chr19-3770753-CCCCGGG-C
• rs549932754
• NM_001319074.4:c.417_422delCCCGGG

Your query was ambiguous. Multiple possible variants found:

• chr19-3770753-CCCCGGG-C
• chr19-3770753-CCCCGGG-CCCCGGGCCCGGG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001319074.4(RAX2):​c.417_422delCCCGGG​(p.Pro140_Gly141del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000131 in 1,530,990 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G139G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: RAX2 NM_001319074.4 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001319074.4.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001319074.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAX2	NM_001319074.4	MANE Select	c.417_422delCCCGGG	p.Pro140_Gly141del	disruptive_inframe_deletion	Exon 3 of 3	NP_001306003.2
	RAX2	NM_032753.4		c.417_422delCCCGGG	p.Pro140_Gly141del	disruptive_inframe_deletion	Exon 3 of 3	NP_116142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAX2	ENST00000555633.3	TSL:1 MANE Select	c.417_422delCCCGGG	p.Pro140_Gly141del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000450456.3
	RAX2	ENST00000555978.5	TSL:1	c.417_422delCCCGGG	p.Pro140_Gly141del	disruptive_inframe_deletion	Exon 3 of 3	ENSP00000450687.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1378794 Hom.: 0 AF XY: 0.00000147 AC XY: 1 AN XY: 680382

African (AFR) AF: 0.00 AC: 0 AN: 30740

American (AMR) AF: 0.00 AC: 0 AN: 35458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24938

East Asian (EAS) AF: 0.00 AC: 0 AN: 35234

South Asian (SAS) AF: 0.00 AC: 0 AN: 79006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5042

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076632

Other (OTH) AF: 0.00 AC: 0 AN: 57576

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=182/18	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs549932754; hg19: chr19-3770751;