Genetic Variant RGPD2:p.Arg454Gln (chr2-87795761-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001078170.3(RGPD2):c.1361G>A(p.Arg454Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 1 hom., cov: 0)

Exomes 𝑓: 0.00084 ( 192 hom. )

Failed GnomAD Quality Control

Consequence

RGPD2
NM_001078170.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.43

Publications

0 publications found

Variant links:

Genes affected

RGPD2 (HGNC:32415): (RANBP2 like and GRIP domain containing 2) Predicted to contribute to GTPase activator activity. Predicted to be involved in NLS-bearing protein import into nucleus. Predicted to be part of nuclear pore. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RGPD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07539886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGPD2	NM_001078170.3 link	c.1361G>A	p.Arg454Gln	missense_variant	Exon 10 of 23	ENST00000398146.5	NP_001071638.2	P0DJD1B4DYH0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGPD2	ENST00000398146.5 link	c.1361G>A	p.Arg454Gln	missense_variant	Exon 10 of 23	1	NM_001078170.3	ENSP00000381214.3		P0DJD1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

25390

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000296

Gnomad OTH

AF:

0.00340

GnomAD2 exomes

AF:

0.000545

AC:

AN:

22014

AF XY:

0.000610

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.000601

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000839

AC:

516

AN:

614896

Hom.:

192

Cov.:

AF XY:

0.000841

AC XY:

257

AN XY:

305410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17412

American (AMR)

AF:

0.00

AC:

AN:

9946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12028

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

23088

European-Finnish (FIN)

AF:

0.000610

AC:

AN:

24584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1640

European-Non Finnish (NFE)

AF:

0.000982

AC:

493

AN:

502124

Other (OTH)

AF:

0.000333

AC:

AN:

24036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

100

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000197

AC:

AN:

25390

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

AN XY:

11662

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8072

American (AMR)

AF:

0.00

AC:

AN:

1262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

734

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

994

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000296

AC:

AN:

13524

Other (OTH)

AF:

0.00340

AC:

AN:

294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.592

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:

0.00

Hom.:

ExAC

AF:

0.000386

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1361G>A (p.R454Q) alteration is located in exon 10 (coding exon 10) of the RGPD2 gene. This alteration results from a G to A substitution at nucleotide position 1361, causing the arginine (R) at amino acid position 454 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.025

T;.

Eigen

Benign

0.19

Eigen_PC

Benign

0.071

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.075

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

3.4

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-2.2

N;.

REVEL

Benign

0.13

Sift

Benign

0.13

T;.

Sift4G

Pathogenic

0.0

D;.

Vest4

0.24

MutPred

0.41

Loss of loop (P = 0.0022);Loss of loop (P = 0.0022);

MVP

0.21

ClinPred

0.28

GERP RS

2.4

Varity_R

0.19

gMVP

0.055

Mutation Taster

=284/16

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over