Genetic Variant NM_006915.3:c.-44G>C (chrX-46837057-G-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

1 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 -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 VariationId is 368304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 183 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.-44G>C		5_prime_UTR	Exon 1 of 5	NP_008846.2	O75695

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RP2	ENST00000218340.4	TSL:1 MANE Select	c.-44G>C	5_prime_UTR	Exon 1 of 5	ENSP00000218340.3	O75695
RP2	ENST00000891112.1		c.-44G>C	5_prime_UTR	Exon 1 of 6	ENSP00000561171.1
RP2	ENST00000949778.1		c.-44G>C	5_prime_UTR	Exon 1 of 4	ENSP00000619837.1

Frequencies

GnomAD3 genomes

AF:

0.00163

AC:

183

AN:

112464

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000723

AC:

AN:

114779

AF XY:

0.000368

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 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

African (AFR)

AF:

0.00675

AC:

164

AN:

24301

American (AMR)

AF:

0.00122

AC:

AN:

27871

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18411

East Asian (EAS)

AF:

0.00

AC:

AN:

26962

South Asian (SAS)

AF:

0.0000407

AC:

AN:

49080

European-Finnish (FIN)

AF:

0.000106

AC:

AN:

37590

Middle Eastern (MID)

AF:

0.00275

AC:

AN:

4005

European-Non Finnish (NFE)

AF:

0.000194

AC:

153

AN:

788059

Other (OTH)

AF:

0.00109

AC:

AN:

43250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00163

AC:

183

AN:

112517

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

AN XY:

34679

show subpopulations

African (AFR)

AF:

0.00509

AC:

158

AN:

31062

American (AMR)

AF:

0.00112

AC:

AN:

10706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6164

Middle Eastern (MID)

AF:

0.00913

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000188

AC:

AN:

53213

Other (OTH)

AF:

0.000653

AC:

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000912

Hom.:

Bravo

AF:

0.00202

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.4

(source)

DANN

Benign

0.69

PhyloP100

0.60

PromoterAI

-0.048

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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