chr19-3770767-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_001319074.4(RAX2):​c.409G>T​(p.Gly137Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,376,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: RAX2 NM_001319074.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 0 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25067502).

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.409G>T	p.Gly137Cys	missense	Exon 3 of 3	NP_001306003.2
	RAX2	NM_032753.4		c.409G>T	p.Gly137Cys	missense	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.409G>T	p.Gly137Cys	missense	Exon 3 of 3	ENSP00000450456.3
	RAX2	ENST00000555978.5	TSL:1	c.409G>T	p.Gly137Cys	missense	Exon 3 of 3	ENSP00000450687.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1376258 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 678922

African (AFR) AF: 0.00 AC: 0 AN: 30458

American (AMR) AF: 0.00 AC: 0 AN: 35240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24808

East Asian (EAS) AF: 0.00 AC: 0 AN: 35044

South Asian (SAS) AF: 0.00 AC: 0 AN: 78826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4902

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075594

Other (OTH) AF: 0.00 AC: 0 AN: 57442

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.14	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.13	T
Polyphen		0.90	P
Vest4		0.36
MutPred		0.32		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.30
MPC		0.33
ClinPred		0.69	D
GERP RS		2.8
Varity_R		0.12
gMVP		0.46
Mutation Taster		=29/71	disease causing

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; COSMIC: COSV57519575; COSMIC: COSV57519575;