chr20-2860283-G-A

Variant names:

• chr20-2860283-G-A
• rs2297048
• NM_022575.4:c.285G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022575.4(VPS16):​c.285G>A​(p.Glu95Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,614,112 control chromosomes in the GnomAD database, including 828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (123 hom., cov: 32)
  • Exomes 𝑓: 0.010 (705 hom.)
• Consequence: VPS16 NM_022575.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.962
• Publications: 5 publications found

Genes affected

VPS16 (HGNC:14584): (VPS16 core subunit of CORVET and HOPS complexes) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human homolog of yeast class C Vps16 protein. The mammalian class C Vps proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2009]

VPS16 Gene-Disease associations (from GenCC):

• dystonia 30

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• isolated dystonia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 20-2860283-G-A is Benign according to our data. Variant chr20-2860283-G-A is described in ClinVar as Benign. ClinVar VariationId is 1272504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.962 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0857 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022575.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS16	NM_022575.4	MANE Select	c.285G>A	p.Glu95Glu	synonymous	Exon 4 of 24	NP_072097.2
	VPS16	NM_080413.3		c.285G>A	p.Glu95Glu	synonymous	Exon 4 of 20	NP_536338.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS16	ENST00000380445.8	TSL:1 MANE Select	c.285G>A	p.Glu95Glu	synonymous	Exon 4 of 24	ENSP00000369810.3
	VPS16	ENST00000380469.7	TSL:2	c.285G>A	p.Glu95Glu	synonymous	Exon 4 of 20	ENSP00000369836.3
	VPS16	ENST00000453689.5	TSL:3	c.16-166G>A		intron	N/A	ENSP00000417031.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2350 AN: 152116 Hom.: 116 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0885

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0855

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0315 AC: 7912 AN: 251390 AF XY: 0.0260

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.0827

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0100 AC: 14677 AN: 1461878 Hom.: 705 Cov.: 33 AF XY: 0.00951 AC XY: 6918 AN XY: 727238

African (AFR) AF: 0.00158 AC: 53 AN: 33480

American (AMR) AF: 0.146 AC: 6544 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26136

East Asian (EAS) AF: 0.0721 AC: 2862 AN: 39700

South Asian (SAS) AF: 0.0127 AC: 1093 AN: 86256

European-Finnish (FIN) AF: 0.0116 AC: 619 AN: 53412

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.00252 AC: 2803 AN: 1112008

Other (OTH) AF: 0.0111 AC: 672 AN: 60394

GnomAD4 genome AF: 0.0155 AC: 2364 AN: 152234 Hom.: 123 Cov.: 32 AF XY: 0.0176 AC XY: 1313 AN XY: 74420

African (AFR) AF: 0.00248 AC: 103 AN: 41540

American (AMR) AF: 0.0897 AC: 1371 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.0851 AC: 439 AN: 5158

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4828

European-Finnish (FIN) AF: 0.0161 AC: 171 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00235 AC: 160 AN: 68014

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0108 Hom.: 136

Bravo AF: 0.0221

Asia WGS AF: 0.0590 AC: 203 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00225

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.6
DANN	Benign	0.78
PhyloP100		0.96
Mutation Taster		=99/1	polymorphism (auto)

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: rs2297048; hg19: chr20-2840929; COSMIC: COSV66795382; COSMIC: COSV66795382;