X-46837130-G-A

Position:

• chrX-46837130-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_006915.3(RP2):​c.30G>A​(p.Lys10=) 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

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]

ACMG classification

Verdict is Benign. Variant got -12 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 id is 289614.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=1.48 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000212 (224/1056113) while in subpopulation MID AF= 0.00147 (6/4092). AF 95% confidence interval is 0.000639. There are 0 homozygotes in gnomad4_exome. There are 76 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP2	NM_006915.3	c.30G>A	p.Lys10=	synonymous_variant	1/5	ENST00000218340.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP2	ENST00000218340.4	c.30G>A	p.Lys10=	synonymous_variant	1/5	1	NM_006915.3	P1

Frequencies

GnomAD3 genomes AF: 0.000196 AC: 22 AN: 112127 Hom.: 0 Cov.: 23 AF XY: 0.000233 AC XY: 8 AN XY: 34281

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

GnomAD3 exomes AF: 0.000470 AC: 55 AN: 117092 Hom.: 0 AF XY: 0.000441 AC XY: 18 AN XY: 40836

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00750

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000731

Gnomad4 OTH exome AF: 0.000405

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00677

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00122 Hom.: 9

Bravo AF: 0.000200

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	RP2: BP4, BP7 -

Retinitis pigmentosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs782402689; hg19: chrX-46696565; COSMIC: COSV54462065;