chr19-3770967-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001319074.4(RAX2):c.217-8C>T variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.00005479

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.18

Publications

7 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: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
RAX2	NM_001319074.4 link	c.217-8C>T		splice_region_variant, intron_variant	Intron 2 of 2	ENST00000555633.3	NP_001306003.2	Q96IS3
RAX2	NM_032753.4 link	c.217-8C>T		splice_region_variant, intron_variant	Intron 2 of 2		NP_116142.1	Q96IS3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAX2	ENST00000555633.3 link	c.217-8C>T		splice_region_variant, intron_variant	Intron 2 of 2	1	NM_001319074.4	ENSP00000450456.3		Q96IS3
RAX2	ENST00000555978.5 link	c.217-8C>T		splice_region_variant, intron_variant	Intron 2 of 2	1		ENSP00000450687.2		Q96IS3

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

GnomAD2 exomes

AF:

0.158

AC:

24393

AN:

154002

AF XY:

0.163

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 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

African (AFR)

AF:

0.123

AC:

4009

AN:

32564

American (AMR)

AF:

0.130

AC:

4885

AN:

37680

Ashkenazi Jewish (ASJ)

AF:

0.157

AC:

3986

AN:

25318

East Asian (EAS)

AF:

0.0281

AC:

1060

AN:

37698

South Asian (SAS)

AF:

0.159

AC:

12920

AN:

81208

European-Finnish (FIN)

AF:

0.161

AC:

5548

AN:

34456

Middle Eastern (MID)

AF:

0.214

AC:

1175

AN:

5500

European-Non Finnish (NFE)

AF:

0.182

AC:

197225

AN:

1085808

Other (OTH)

AF:

0.165

AC:

9649

AN:

58500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

11214

22428

33641

44855

56069

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6846

13692

20538

27384

34230

<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:

0.151

AC:

23018

AN:

152186

Hom.:

1885

Cov.:

AF XY:

0.150

AC XY:

11186

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.121

AC:

5007

AN:

41522

American (AMR)

AF:

0.138

AC:

2108

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.161

AC:

559

AN:

3470

East Asian (EAS)

AF:

0.0251

AC:

130

AN:

5170

South Asian (SAS)

AF:

0.155

AC:

751

AN:

4830

European-Finnish (FIN)

AF:

0.156

AC:

1655

AN:

10618

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.180

AC:

12229

AN:

67968

Other (OTH)

AF:

0.163

AC:

345

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1029

2059

3088

4118

5147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.169

Hom.:

411

Bravo

AF:

0.150

Asia WGS

AF:

0.0940

AC:

328

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 29, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cone-rod dystrophy 11

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.0

(source)

DANN

Benign

0.92

PhyloP100

2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over