Genetic Variant RABEPK:p.Thr125Lys (chr9-125220548-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005833.4(RABEPK):c.374C>A(p.Thr125Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RABEPK
NM_005833.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.127

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06524032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RABEPK	NM_005833.4 link	c.374C>A	p.Thr125Lys	missense_variant	Exon 5 of 8	ENST00000373538.8	NP_005824.2	Q7Z6M1-1A0A024R8A0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RABEPK	ENST00000373538.8 link	c.374C>A	p.Thr125Lys	missense_variant	Exon 5 of 8	1	NM_005833.4	ENSP00000362639.3		Q7Z6M1-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461008

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726794

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374C>A (p.T125K) alteration is located in exon 5 (coding exon 4) of the RABEPK gene. This alteration results from a C to A substitution at nucleotide position 374, causing the threonine (T) at amino acid position 125 to be replaced by a lysine (K). 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

0.093

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.38

CADD

Benign

4.7

DANN

Benign

0.71

DEOGEN2

Benign

0.0047

T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.26

T;.

M_CAP

Benign

0.0084

MetaRNN

Benign

0.065

T;T

MetaSVM

Benign

-0.99

PROVEAN

Benign

0.98

.;N

REVEL

Benign

0.062

Sift

Pathogenic

0.0

.;D

Sift4G

Benign

0.70

T;T

Polyphen

0.0050

B;B

Vest4

0.24

MutPred

0.44

Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);

MVP

0.13

ClinPred

0.14

GERP RS

2.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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