rs782402689

Variant names:

• chrX-46837130-G-A
• rs782402689
• NM_006915.3:c.30G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_006915.3(RP2):​c.30G>A​(p.Lys10Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,168,298 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 84 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00021 (0 hom. 76 hem.)
• Consequence: RP2 NM_006915.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.48
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae)
• RP2-related retinopathy

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-46837130-G-A is Benign according to our data. Variant chrX-46837130-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289614.
• BP7: Synonymous conserved (PhyloP=1.48 with no splicing effect.
• BS2: High AC in GnomAd4 at 22 XL,AD gene.

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.30G>A	p.Lys10Lys	synonymous	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.30G>A	p.Lys10Lys	synonymous	Exon 1 of 5	ENSP00000218340.3	O75695
	RP2	ENST00000891112.1		c.30G>A	p.Lys10Lys	synonymous	Exon 1 of 6	ENSP00000561171.1
	RP2	ENST00000949778.1		c.30G>A	p.Lys10Lys	synonymous	Exon 1 of 4	ENSP00000619837.1

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 22 AN: 112127 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00677

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000470 AC: 55 AN: 117092 AF XY: 0.000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00759

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.000600

GnomAD4 exome AF: 0.000212 AC: 224 AN: 1056113 Hom.: 0 Cov.: 30 AF XY: 0.000220 AC XY: 76 AN XY: 345515

African (AFR) AF: 0.00 AC: 0 AN: 24971

American (AMR) AF: 0.00 AC: 0 AN: 28228

Ashkenazi Jewish (ASJ) AF: 0.00750 AC: 140 AN: 18666

East Asian (EAS) AF: 0.00 AC: 0 AN: 27243

South Asian (SAS) AF: 0.00 AC: 0 AN: 49956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37775

Middle Eastern (MID) AF: 0.00147 AC: 6 AN: 4092

European-Non Finnish (NFE) AF: 0.0000731 AC: 60 AN: 820696

Other (OTH) AF: 0.000405 AC: 18 AN: 44486

GnomAD4 genome AF: 0.000196 AC: 22 AN: 112185 Hom.: 0 Cov.: 23 AF XY: 0.000233 AC XY: 8 AN XY: 34349

African (AFR) AF: 0.00 AC: 0 AN: 30924

American (AMR) AF: 0.00 AC: 0 AN: 10667

Ashkenazi Jewish (ASJ) AF: 0.00677 AC: 18 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.00 AC: 0 AN: 2670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6106

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53185

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.00122 Hom.: 9

Bravo AF: 0.000200

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.95
PhyloP100		1.5
PromoterAI		-0.079	Neutral
Mutation Taster		=99/1	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: rs782402689; hg19: chrX-46696565; COSMIC: COSV54462065;