X-46837119-A-C

Position:

• chrX-46837119-A-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006915.3(RP2):​c.19A>C​(p.Lys7Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000758 in 1,055,295 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000076 (0 hom. 4 hem.)
• Consequence: RP2 NM_006915.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.30

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39320773).
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RP2	NM_006915.3	c.19A>C	p.Lys7Gln	missense_variant	1/5	ENST00000218340.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RP2	ENST00000218340.4	c.19A>C	p.Lys7Gln	missense_variant	1/5	1	NM_006915.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000758 AC: 8 AN: 1055295 Hom.: 0 Cov.: 30 AF XY: 0.0000116 AC XY: 4 AN XY: 345315

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000975

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 28, 2021

This sequence change replaces lysine with glutamine at codon 7 of the RP2 protein (p.Lys7Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with RP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 866701). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jun 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.45
Sift	Benign	0.031	D
Sift4G	Uncertain	0.027	D
Polyphen		0.99	D
Vest4		0.16
MVP		0.82
MPC		0.87
ClinPred		0.92	D
GERP RS		3.7
Varity_R		0.51
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1924520196; hg19: chrX-46696554;