19-3770753-CCCCGGG-CCCCGGGCCCGGG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BS1_SupportingBS2

The NM_001319074.4(RAX2):c.417_422dupCCCGGG(p.Gly141_Leu142insProGly) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,531,106 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 4 hom. )

Consequence

RAX2
NM_001319074.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2B:1

Conservation

PhyloP100: 1.70

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001319074.4.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000144 (22/152312) while in subpopulation SAS AF = 0.00352 (17/4834). AF 95% confidence interval is 0.00224. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAX2	NM_001319074.4 link	c.417_422dupCCCGGG	p.Gly141_Leu142insProGly	disruptive_inframe_insertion	Exon 3 of 3	ENST00000555633.3	NP_001306003.2	Q96IS3
RAX2	NM_032753.4 link	c.417_422dupCCCGGG	p.Gly141_Leu142insProGly	disruptive_inframe_insertion	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.417_422dupCCCGGG	p.Gly141_Leu142insProGly	disruptive_inframe_insertion	Exon 3 of 3	1	NM_001319074.4	ENSP00000450456.3		Q96IS3
RAX2	ENST00000555978.5 link	c.417_422dupCCCGGG	p.Gly141_Leu142insProGly	disruptive_inframe_insertion	Exon 3 of 3	1		ENSP00000450687.2		Q96IS3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

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:

0.00351

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000733

AC:

AN:

125538

AF XY:

0.000929

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000414

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000858

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000339

AC:

468

AN:

1378794

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

302

AN XY:

680382

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

30740

Gnomad4 AMR exome

AF:

0.0000282

AC:

AN:

35458

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

24938

Gnomad4 EAS exome

AF:

0.0000284

AC:

AN:

35234

Gnomad4 SAS exome

AF:

0.00433

AC:

342

AN:

79004

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

34168

Gnomad4 NFE exome

AF:

0.0000975

AC:

105

AN:

1076634

Gnomad4 Remaining exome

AF:

0.000330

AC:

AN:

57576

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

AF:

0.000144

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00352

AC:

0.00351676

AN:

0.00351676

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000588

AC:

0.0000588166

AN:

0.0000588166

Gnomad4 OTH

AF:

0.000473

AC:

0.000473485

AN:

0.000473485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.0000480

Hom.:

Asia WGS

AF:

0.00202

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cone-rod dystrophy 11

Pathogenic:2

May 15, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Sep 24, 2020

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant (reported as, 140P_141Gdup) was previously reported in a patient with cone-rod dystrophy in heterozygous state and also identified in the proband's mother and two siblings with normal vision but possibility of mild CORD could not be excluded in them as mentioned in the article. Functional studies using co-immunoprecipitation analysis suggested proteins with the variant have decreased interaction with Crx and increased transactivation activity [PMID: 15028672]. -

not provided

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=81/19

disease causing (ClinVar)

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over