Variant chrX-17029574-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004726.3(REPS2):c.722C>T(p.Ser241Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000067 in 1,209,461 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., 17 hem., cov: 24)

Exomes 𝑓: 0.000034 ( 0 hom. 13 hem. )

Consequence

REPS2
NM_004726.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.791

Variant links:

Genes affected

REPS2 (HGNC:9963): (RALBP1 associated Eps domain containing 2) The product of this gene is part of a protein complex that regulates the endocytosis of growth factor receptors. The encoded protein directly interacts with a GTPase activating protein that functions downstream of the small G protein Ral. Its expression can negatively affect receptor internalization and inhibit growth factor signaling. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

REPS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01710409).

BS2

High Hemizygotes in GnomAd4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REPS2	NM_004726.3 linkuse as main transcript	c.722C>T	p.Ser241Leu	missense_variant	5/18	ENST00000357277.8	NP_004717.2	Q8NFH8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REPS2	ENST00000357277.8 linkuse as main transcript	c.722C>T	p.Ser241Leu	missense_variant	5/18	1	NM_004726.3	ENSP00000349824.3		Q8NFH8-1
REPS2	ENST00000303843.7 linkuse as main transcript	c.719C>T	p.Ser240Leu	missense_variant	5/18	1		ENSP00000306033.7		Q8NFH8-4

Frequencies

GnomAD3 genomes

AF:

0.000390

AC:

AN:

112684

Hom.:

Cov.:

AF XY:

0.000488

AC XY:

AN XY:

34822

show subpopulations

Gnomad AFR

AF:

0.00142

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000105

AC:

AN:

181206

Hom.:

AF XY:

0.0000608

AC XY:

AN XY:

65760

show subpopulations

Gnomad AFR exome

AF:

0.00139

Gnomad AMR exome

AF:

0.0000368

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000337

AC:

AN:

1096723

Hom.:

Cov.:

AF XY:

0.0000359

AC XY:

AN XY:

362133

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

Gnomad4 AMR exome

AF:

0.0000285

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000390

AC:

AN:

112738

Hom.:

Cov.:

AF XY:

0.000487

AC XY:

AN XY:

34886

show subpopulations

Gnomad4 AFR

AF:

0.00142

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000184

Hom.:

Bravo

AF:

0.000355

ESP6500AA

AF:

0.00235

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

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

Jun 22, 2021

The c.722C>T (p.S241L) alteration is located in exon 5 (coding exon 5) of the REPS2 gene. This alteration results from a C to T substitution at nucleotide position 722, causing the serine (S) at amino acid position 241 to be replaced by a leucine (L). 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

0.070

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.029

Sift

Benign

0.054

T;D

Sift4G

Uncertain

0.033

D;D

Polyphen

0.085

B;P

Vest4

0.23

MVP

0.16

MPC

0.34

ClinPred

0.021

GERP RS

3.7

Varity_R

0.13

gMVP

0.32

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

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