Variant 9-125227961-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005833.4(RABEPK):c.578G>A(p.Arg193Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000659 in 1,608,612 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: 𝑓 0.000086 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

RABEPK
NM_005833.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.97

Variant links:

Genes affected

RABEPK (HGNC:16896): (Rab9 effector protein with kelch motifs) Predicted to be involved in receptor-mediated endocytosis and vesicle docking involved in exocytosis. Predicted to be located in cytoplasmic vesicle; cytosol; and trans-Golgi network membrane. [provided by Alliance of Genome Resources, Apr 2022]

RABEPK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RABEPK	NM_005833.4 linkuse as main transcript	c.578G>A	p.Arg193Gln	missense_variant	6/8	ENST00000373538.8	NP_005824.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RABEPK	ENST00000373538.8 linkuse as main transcript	c.578G>A	p.Arg193Gln	missense_variant	6/8	1	NM_005833.4	ENSP00000362639	P1	Q7Z6M1-1
RABEPK	ENST00000394125.8 linkuse as main transcript	c.578G>A	p.Arg193Gln	missense_variant	7/9	1		ENSP00000377683	P1	Q7Z6M1-1
RABEPK	ENST00000259460.12 linkuse as main transcript	c.425G>A	p.Arg142Gln	missense_variant	6/8	1		ENSP00000259460		Q7Z6M1-2
RABEPK	ENST00000628863.2 linkuse as main transcript	c.*184G>A		3_prime_UTR_variant	8/10	5		ENSP00000487422

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000525

AC:

AN:

247490

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000269

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000356

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000638

AC:

AN:

1456576

Hom.:

Cov.:

AF XY:

0.0000704

AC XY:

AN XY:

724578

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.000226

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:

0.0000676

Gnomad4 OTH exome

AF:

0.0000832

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000488

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000110

EpiControl

AF:

0.000120

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2023

The c.578G>A (p.R193Q) alteration is located in exon 6 (coding exon 5) of the RABEPK gene. This alteration results from a G to A substitution at nucleotide position 578, causing the arginine (R) at amino acid position 193 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

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.38

T;.;T

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;.

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

4.2

H;.;H

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.012

D;D;D

Polyphen

0.87

P;D;P

Vest4

0.98

MVP

0.99

MPC

0.23

ClinPred

0.99

GERP RS

5.2

Varity_R

0.31

gMVP

0.88

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over