2-63933730-G-C

Position:

• chr2-63933730-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016516.3(VPS54):​c.1682C>G​(p.Ser561Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00516 in 1,613,732 control chromosomes in the GnomAD database, including 348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.027 (174 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (174 hom.)
• Consequence: VPS54 NM_016516.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.96

Genes affected

VPS54 (HGNC:18652): (VPS54 subunit of GARP complex) This gene encodes for a protein that in yeast forms part of a trimeric vacuolar-protein-sorting complex that is required for retrograde transport of proteins from prevacuoles to the late Golgi compartment. As in yeast, mammalian Vps54 proteins contain a coiled-coil region and dileucine motifs. Alternative splicing results in multiple transcript variants encoding different isoforms [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026147962).
• BP6: Variant 2-63933730-G-C is Benign according to our data. Variant chr2-63933730-G-C is described in ClinVar as [Benign]. Clinvar id is 775722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-63933730-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS54	NM_016516.3	c.1682C>G	p.Ser561Cys	missense_variant	12/23	ENST00000272322.9	NP_057600.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS54	ENST00000272322.9	c.1682C>G	p.Ser561Cys	missense_variant	12/23	5	NM_016516.3	ENSP00000272322	P1
VPS54	ENST00000409558.8	c.1646C>G	p.Ser549Cys	missense_variant	12/23	1		ENSP00000386980
VPS54	ENST00000354504.7	c.1223C>G	p.Ser408Cys	missense_variant	9/20	1		ENSP00000346499

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4102 AN: 152114 Hom.: 175 Cov.: 32

Gnomad AFR AF: 0.0943

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00930

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00721 AC: 1807 AN: 250784 Hom.: 78 AF XY: 0.00542 AC XY: 734 AN XY: 135502

Gnomad AFR exome AF: 0.0997

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00288 AC: 4215 AN: 1461500 Hom.: 174 Cov.: 30 AF XY: 0.00246 AC XY: 1791 AN XY: 727048

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.00508

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.00571

GnomAD4 genome AF: 0.0270 AC: 4104 AN: 152232 Hom.: 174 Cov.: 32 AF XY: 0.0262 AC XY: 1949 AN XY: 74458

Gnomad4 AFR AF: 0.0941

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00426 Hom.: 18

Bravo AF: 0.0307

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0813 AC: 358

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00841 AC: 1021

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.036	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.58
MVP		0.068
MPC		0.20
ClinPred		0.034	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.34

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

Other links and lift over

dbSNP: rs34015596; hg19: chr2-64160864;