chr6-33268596-T-C

Variant names:

• chr6-33268596-T-C
• rs762054139
• NM_022553.6:c.602A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022553.6(VPS52):​c.602A>G​(p.Glu201Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS52 NM_022553.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93
• Publications: 0 publications found

Genes affected

VPS52 (HGNC:10518): (VPS52 subunit of GARP complex) This gene encodes a protein that is similar to the yeast suppressor of actin mutations 2 gene. The yeast protein forms a subunit of the tetrameric Golgi-associated retrograde protein complex that is involved in vesicle trafficking from from both early and late endosomes, back to the trans-Golgi network. This gene is located on chromosome 6 in a head-to-head orientation with the gene encoding ribosomal protein S18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS52	NM_022553.6	c.602A>G	p.Glu201Gly	missense_variant	Exon 7 of 20	ENST00000445902.3	NP_072047.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS52	ENST00000445902.3	c.602A>G	p.Glu201Gly	missense_variant	Exon 7 of 20	1	NM_022553.6	ENSP00000409952.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000817 AC: 2 AN: 244948 AF XY: 0.00000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.602A>G (p.E201G) alteration is located in exon 7 (coding exon 7) of the VPS52 gene. This alteration results from a A to G substitution at nucleotide position 602, causing the glutamic acid (E) at amino acid position 201 to be replaced by a glycine (G). 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	0.21
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.58		Loss of disorder (P = 0.0684);
MVP		0.62
MPC		1.6
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.59
gMVP		0.59
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs762054139; hg19: chr6-33236373;