X-46837066-A-G

Variant names:

• chrX-46837066-A-G
• rs909119773
• NM_006915.3:c.-35A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006915.3(RP2):​c.-35A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,142,258 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000051 (0 hom. 18 hem.)
• Consequence: RP2 NM_006915.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0650
• Publications: 1 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=-0.81).
• BS2: High AC in GnomAdExome4 at 53 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.-35A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_008846.2	O75695
	RP2	NM_006915.3	MANE Select	c.-35A>G		5_prime_UTR	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.-35A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000218340.3	O75695
	RP2	ENST00000218340.4	TSL:1 MANE Select	c.-35A>G		5_prime_UTR	Exon 1 of 5	ENSP00000218340.3	O75695
	RP2	ENST00000891112.1		c.-35A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000561171.1

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112307 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000348 AC: 4 AN: 114937 AF XY: 0.0000489

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000515 AC: 53 AN: 1029951 Hom.: 0 Cov.: 26 AF XY: 0.0000555 AC XY: 18 AN XY: 324473

African (AFR) AF: 0.00 AC: 0 AN: 24502

American (AMR) AF: 0.00 AC: 0 AN: 27881

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18477

East Asian (EAS) AF: 0.00 AC: 0 AN: 27012

South Asian (SAS) AF: 0.00 AC: 0 AN: 49347

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37595

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4028

European-Non Finnish (NFE) AF: 0.0000665 AC: 53 AN: 797482

Other (OTH) AF: 0.00 AC: 0 AN: 43627

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112307 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34473

African (AFR) AF: 0.00 AC: 0 AN: 30935

American (AMR) AF: 0.00 AC: 0 AN: 10684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.00 AC: 0 AN: 2723

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000564 AC: 3 AN: 53198

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.1
DANN	Benign	0.69
PhyloP100		0.065
PromoterAI		-0.021	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs909119773; hg19: chrX-46696501;