chrX-17022249-G-C

Position:

• chrX-17022249-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004726.3(REPS2):​c.524G>C​(p.Arg175Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000912 in 1,096,441 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: REPS2 NM_004726.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
REPS2	NM_004726.3	c.524G>C	p.Arg175Thr	missense_variant	3/18	ENST00000357277.8	NP_004717.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
REPS2	ENST00000357277.8	c.524G>C	p.Arg175Thr	missense_variant	3/18	1	NM_004726.3	ENSP00000349824.3
REPS2	ENST00000303843.7	c.524G>C	p.Arg175Thr	missense_variant	3/18	1		ENSP00000306033.7
REPS2	ENST00000481792.1	n.316G>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096441 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 361859

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2023

The c.524G>C (p.R175T) alteration is located in exon 3 (coding exon 3) of the REPS2 gene. This alteration results from a G to C substitution at nucleotide position 524, causing the arginine (R) at amino acid position 175 to be replaced by a threonine (T). 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	0.18
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.15
Sift	Benign	0.29	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.32	B;P
Vest4		0.64
MutPred		0.32		Loss of stability (P = 0.028);Loss of stability (P = 0.028);
MVP		0.61
MPC		0.67
ClinPred		0.80	D
GERP RS		5.7
Varity_R		0.52
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-17040372;