19-3770767-C-G

Variant names:

• chr19-3770767-C-G
• rs121908281
• NM_001319074.4:c.409G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001319074.4(RAX2):​c.409G>C​(p.Gly137Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G137G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAX2 NM_001319074.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.13
• Publications: 3 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835
• PP5: Variant 19-3770767-C-G is Pathogenic according to our data. Variant chr19-3770767-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1241.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAX2	NM_001319074.4	c.409G>C	p.Gly137Arg	missense_variant	Exon 3 of 3	ENST00000555633.3	NP_001306003.2
RAX2	NM_032753.4	c.409G>C	p.Gly137Arg	missense_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.409G>C	p.Gly137Arg	missense_variant	Exon 3 of 3	1	NM_001319074.4	ENSP00000450456.3
RAX2	ENST00000555978.5	c.409G>C	p.Gly137Arg	missense_variant	Exon 3 of 3	1		ENSP00000450687.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cone-rod dystrophy 11 Pathogenic:1

May 15, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.57	.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	1.9	L;L
PhyloP100		1.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.62	.;N
REVEL	Pathogenic	0.65
Sift	Benign	0.050	.;D
Sift4G	Benign	0.29	T;T
Polyphen		0.54	P;P
Vest4		0.57
MutPred		0.76		Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);
MVP		0.73
MPC		0.34
ClinPred		0.37	T
GERP RS		2.8
Varity_R		0.066
gMVP		0.40
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs121908281; hg19: chr19-3770765;