Genetic Variant RP2:c.-44G>C (chrX-46837057-G-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006915.3(RP2):c.-44G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,132,046 control chromosomes in the GnomAD database, including 3 homozygotes. There are 176 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., 53 hem., cov: 23)

Exomes 𝑓: 0.00041 ( 2 hom. 123 hem. )

Consequence

RP2
NM_006915.3 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.599

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant X-46837057-G-C is Benign according to our data. Variant chrX-46837057-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 368304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 53 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RP2	NM_006915.3 link	c.-44G>C		5_prime_UTR_variant	Exon 1 of 5	ENST00000218340.4	NP_008846.2	O75695A0A1B2JLU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RP2	ENST00000218340 link	c.-44G>C		5_prime_UTR_variant	Exon 1 of 5	1	NM_006915.3	ENSP00000218340.3		O75695

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

183

AN:

112464

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

AN XY:

34616

show subpopulations

Gnomad AFR

AF:

0.00510

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00833

Gnomad NFE

AF:

0.000188

Gnomad OTH

AF:

0.000661

GnomAD3 exomes

AF:

0.000723

AC:

AN:

114779

Hom.:

AF XY:

0.000368

AC XY:

AN XY:

40813

show subpopulations

Gnomad AFR exome

AF:

0.00576

Gnomad AMR exome

AF:

0.00108

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000140

Gnomad FIN exome

AF:

0.000171

Gnomad NFE exome

AF:

0.000136

Gnomad OTH exome

AF:

0.00335

GnomAD4 exome

AF:

0.000407

AC:

415

AN:

1019529

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

123

AN XY:

315469

show subpopulations

Gnomad4 AFR exome

AF:

0.00675

Gnomad4 AMR exome

AF:

0.00122

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000407

Gnomad4 FIN exome

AF:

0.000106

Gnomad4 NFE exome

AF:

0.000194

Gnomad4 OTH exome

AF:

0.00109

GnomAD4 genome

AF:

0.00163

AC:

183

AN:

112517

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

AN XY:

34679

show subpopulations

Gnomad4 AFR

AF:

0.00509

Gnomad4 AMR

AF:

0.00112

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000188

Gnomad4 OTH

AF:

0.000653

Alfa

AF:

0.000912

Hom.:

Bravo

AF:

0.00202

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Retinitis pigmentosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-0.81

CADD

Benign

8.4

DANN

Benign

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over