Genetic Variant RABEP2:p.Leu449Pro (chr16-28906096-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024816.3(RABEP2):c.1346T>C(p.Leu449Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,444,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

RABEP2
NM_024816.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.93

Publications

0 publications found

Variant links:

Genes affected

RABEP2 (HGNC:24817): (rabaptin, RAB GTPase binding effector protein 2) Predicted to enable GTPase activator activity and growth factor activity. Involved in regulation of cilium assembly. Located in cytosol; intracellular membrane-bounded organelle; and microtubule organizing center. [provided by Alliance of Genome Resources, Apr 2022]

RABEP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RABEP2	NM_024816.3 link	c.1346T>C	p.Leu449Pro	missense_variant	Exon 9 of 13	ENST00000358201.9	NP_079092.2	Q9H5N1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RABEP2	ENST00000358201.9 link	c.1346T>C	p.Leu449Pro	missense_variant	Exon 9 of 13	1	NM_024816.3	ENSP00000350934.4	Q9H5N1-1
RABEP2	ENST00000357573.10 link	c.1250T>C	p.Leu417Pro	missense_variant	Exon 8 of 11	1		ENSP00000350186.6	Q9H5N1-2
RABEP2	ENST00000544477.5 link	c.1133T>C	p.Leu378Pro	missense_variant	Exon 8 of 12	2		ENSP00000442798.1	B4DHR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000432

AC:

AN:

208254

AF XY:

0.0000612

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000384

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000335

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1444756

Hom.:

Cov.:

AF XY:

0.00000976

AC XY:

AN XY:

717492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33204

American (AMR)

AF:

0.00

AC:

AN:

41824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25696

East Asian (EAS)

AF:

0.0000771

AC:

AN:

38922

South Asian (SAS)

AF:

0.00

AC:

AN:

84282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50730

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00000996

AC:

AN:

1104748

Other (OTH)

AF:

0.0000168

AC:

AN:

59686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000500

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1346T>C (p.L449P) alteration is located in exon 9 (coding exon 9) of the RABEP2 gene. This alteration results from a T to C substitution at nucleotide position 1346, causing the leucine (L) at amino acid position 449 to be replaced by a proline (P). 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

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

.;D;.

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.7

.;M;.

PhyloP100

2.9

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;D

Sift4G

Benign

0.28

T;T;D

Polyphen

1.0

D;D;D

Vest4

0.87

MutPred

0.84

.;Loss of stability (P = 0.0346);.;

MVP

0.93

MPC

0.85

ClinPred

0.76

GERP RS

5.2

Varity_R

0.90

gMVP

0.86

Mutation Taster

=57/43

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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chr16-28906096-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over