rs79588413

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001319074.4(RAX2):c.217-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,550,918 control chromosomes in the GnomAD database, including 23,436 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 1885 hom., cov: 33)

Exomes 𝑓: 0.17 ( 21551 hom. )

Consequence

RAX2
NM_001319074.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00005479

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.18

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 19-3770967-G-A is Benign according to our data. Variant chr19-3770967-G-A is described in ClinVar as [Benign]. Clinvar id is 96230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAX2	NM_001319074.4 linkuse as main transcript	c.217-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000555633.3
RAX2	NM_032753.4 linkuse as main transcript	c.217-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAX2	ENST00000555633.3 linkuse as main transcript	c.217-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001319074.4	P1
RAX2	ENST00000555978.5 linkuse as main transcript	c.217-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

23000

AN:

152068

Hom.:

1884

Cov.:

show subpopulations

Gnomad AFR

AF:

0.120

Gnomad AMI

AF:

0.199

Gnomad AMR

AF:

0.138

Gnomad ASJ

AF:

0.161

Gnomad EAS

AF:

0.0251

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.165

GnomAD3 exomes

AF:

0.158

AC:

24393

AN:

154002

Hom.:

2151

AF XY:

0.163

AC XY:

13841

AN XY:

85028

show subpopulations

Gnomad AFR exome

AF:

0.129

Gnomad AMR exome

AF:

0.130

Gnomad ASJ exome

AF:

0.161

Gnomad EAS exome

AF:

0.0206

Gnomad SAS exome

AF:

0.162

Gnomad FIN exome

AF:

0.173

Gnomad NFE exome

AF:

0.198

Gnomad OTH exome

AF:

0.182

GnomAD4 exome

AF:

0.172

AC:

240457

AN:

1398732

Hom.:

21551

Cov.:

AF XY:

0.172

AC XY:

118949

AN XY:

692290

show subpopulations

Gnomad4 AFR exome

AF:

0.123

Gnomad4 AMR exome

AF:

0.130

Gnomad4 ASJ exome

AF:

0.157

Gnomad4 EAS exome

AF:

0.0281

Gnomad4 SAS exome

AF:

0.159

Gnomad4 FIN exome

AF:

0.161

Gnomad4 NFE exome

AF:

0.182

Gnomad4 OTH exome

AF:

0.165

GnomAD4 genome

AF:

0.151

AC:

23018

AN:

152186

Hom.:

1885

Cov.:

AF XY:

0.150

AC XY:

11186

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.121

Gnomad4 AMR

AF:

0.138

Gnomad4 ASJ

AF:

0.161

Gnomad4 EAS

AF:

0.0251

Gnomad4 SAS

AF:

0.155

Gnomad4 FIN

AF:

0.156

Gnomad4 NFE

AF:

0.180

Gnomad4 OTH

AF:

0.163

Alfa

AF:

0.169

Hom.:

411

Bravo

AF:

0.150

Asia WGS

AF:

0.0940

AC:

328

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Cone-rod dystrophy 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Age related macular degeneration 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

Cadd

Benign

6.0

Dann

Benign

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000055

dbscSNV1_RF

Benign

0.0060

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

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