X-46837138-A-G

Variant names:

• chrX-46837138-A-G
• rs1238437293
• NM_006915.3:c.38A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006915.3(RP2):​c.38A>G​(p.Lys13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000946 in 1,056,798 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. K13M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.5e-7 (0 hom. 1 hem.)
• Consequence: RP2 NM_006915.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 0 publications found

Genes affected

RP2 (HGNC:10274): (RP2 activator of ARL3 GTPase) The RP2 locus has been implicated as one cause of X-linked retinitis pigmentosa. The predicted gene product shows homology with human cofactor C, a protein involved in the ultimate step of beta-tubulin folding. Progressive retinal degeneration may therefore be due to the accumulation of incorrectly-folded photoreceptor or neuron-specific tubulin isoforms followed by progressive cell death [provided by RefSeq, Jul 2008]

RP2 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• RP2-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08829796).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006915.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP2	NM_006915.3	MANE Select	c.38A>G	p.Lys13Arg	missense	Exon 1 of 5	NP_008846.2	O75695

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RP2	ENST00000218340.4	TSL:1 MANE Select	c.38A>G	p.Lys13Arg	missense	Exon 1 of 5	ENSP00000218340.3	O75695
	RP2	ENST00000891112.1		c.38A>G	p.Lys13Arg	missense	Exon 1 of 6	ENSP00000561171.1
	RP2	ENST00000949778.1		c.38A>G	p.Lys13Arg	missense	Exon 1 of 4	ENSP00000619837.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.46e-7 AC: 1 AN: 1056798 Hom.: 0 Cov.: 30 AF XY: 0.00000289 AC XY: 1 AN XY: 345666

African (AFR) AF: 0.00 AC: 0 AN: 25009

American (AMR) AF: 0.00 AC: 0 AN: 28378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18666

East Asian (EAS) AF: 0.00 AC: 0 AN: 27299

South Asian (SAS) AF: 0.00 AC: 0 AN: 49985

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37801

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4090

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 821056

Other (OTH) AF: 0.00 AC: 0 AN: 44514

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.13
Sift	Benign	0.36	T
Sift4G	Benign	0.48	T
Polyphen		0.0010	B
Vest4		0.071
MutPred		0.20		Loss of ubiquitination at K13 (P = 0.0034)
MVP		0.58
MPC		0.24
ClinPred		0.14	T
GERP RS		2.5
PromoterAI		-0.082	Neutral
Varity_R		0.069
gMVP		0.48
Mutation Taster		=94/6	polymorphism

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: rs1238437293; hg19: chrX-46696573;