NM_006915.3:c.844C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006915.3(RP2):c.844C>T(p.Arg282Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,206,352 control chromosomes in the GnomAD database, including 343 homozygotes. There are 10,033 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.019 ( 34 hom., 570 hem., cov: 23)

Exomes 𝑓: 0.027 ( 309 hom. 9463 hem. )

Consequence

RP2
NM_006915.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.36

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

retinitis pigmentosa 2
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
RP2-related retinopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053629577).

BP6

Variant X-46860063-C-T is Benign according to our data. Variant chrX-46860063-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0191 (2136/111864) while in subpopulation NFE AF = 0.0303 (1609/53066). AF 95% confidence interval is 0.0291. There are 34 homozygotes in GnomAd4. There are 570 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 2136 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.844C>T	p.Arg282Trp	missense	Exon 3 of 5	NP_008846.2	O75695

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RP2	ENST00000218340.4	TSL:1 MANE Select	c.844C>T	p.Arg282Trp	missense	Exon 3 of 5	ENSP00000218340.3	O75695
RP2	ENST00000891112.1		c.844C>T	p.Arg282Trp	missense	Exon 3 of 6	ENSP00000561171.1
RP2	ENST00000949778.1		c.178C>T	p.Arg60Trp	missense	Exon 2 of 4	ENSP00000619837.1

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2139

AN:

111808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00444

Gnomad AMI

AF:

0.00876

Gnomad AMR

AF:

0.0152

Gnomad ASJ

AF:

0.0223

Gnomad EAS

AF:

0.000277

Gnomad SAS

AF:

0.00510

Gnomad FIN

AF:

0.0182

Gnomad MID

AF:

0.0669

Gnomad NFE

AF:

0.0303

Gnomad OTH

AF:

0.0184

GnomAD2 exomes

AF:

0.0182

AC:

3337

AN:

182850

AF XY:

0.0170

show subpopulations

Gnomad AFR exome

AF:

0.00419

Gnomad AMR exome

AF:

0.00822

Gnomad ASJ exome

AF:

0.0178

Gnomad EAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.0184

Gnomad NFE exome

AF:

0.0301

Gnomad OTH exome

AF:

0.0195

GnomAD4 exome

AF:

0.0273

AC:

29927

AN:

1094488

Hom.:

309

Cov.:

AF XY:

0.0263

AC XY:

9463

AN XY:

360050

show subpopulations

African (AFR)

AF:

0.00357

AC:

AN:

26337

American (AMR)

AF:

0.00833

AC:

293

AN:

35171

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

353

AN:

19347

East Asian (EAS)

AF:

0.0000995

AC:

AN:

30143

South Asian (SAS)

AF:

0.00410

AC:

221

AN:

53946

European-Finnish (FIN)

AF:

0.0204

AC:

827

AN:

40508

Middle Eastern (MID)

AF:

0.0298

AC:

123

AN:

4122

European-Non Finnish (NFE)

AF:

0.0321

AC:

26889

AN:

838943

Other (OTH)

AF:

0.0245

AC:

1124

AN:

45971

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

901

1802

2702

3603

4504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1006

2012

3018

4024

5030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0191

AC:

2136

AN:

111864

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

570

AN XY:

34070

show subpopulations

African (AFR)

AF:

0.00443

AC:

137

AN:

30895

American (AMR)

AF:

0.0152

AC:

159

AN:

10493

Ashkenazi Jewish (ASJ)

AF:

0.0223

AC:

AN:

2648

East Asian (EAS)

AF:

0.000278

AC:

AN:

3603

South Asian (SAS)

AF:

0.00511

AC:

AN:

2739

European-Finnish (FIN)

AF:

0.0182

AC:

109

AN:

5977

Middle Eastern (MID)

AF:

0.0642

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0303

AC:

1609

AN:

53066

Other (OTH)

AF:

0.0182

AC:

AN:

1540

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

160

239

319

399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0159

Hom.:

178

Bravo

AF:

0.0176

TwinsUK

AF:

0.0313

AC:

116

ALSPAC

AF:

0.0291

AC:

ESP6500AA

AF:

0.00365

AC:

ESP6500EA

AF:

0.0328

AC:

221

ExAC

AF:

0.0185

AC:

2241

EpiCase

AF:

0.0301

EpiControl

AF:

0.0288

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Retinitis pigmentosa 2 (2)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

PhyloP100

3.4

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.6

REVEL

Benign

0.21

Sift

Benign

0.091

Sift4G

Uncertain

0.040

Polyphen

0.93

Vest4

0.048

MPC

0.38

ClinPred

0.017

GERP RS

3.4

Varity_R

0.23

gMVP

0.53

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over