chr20-2860052-A-T

Variant names:

• chr20-2860052-A-T
• NM_022575.4:c.143-2A>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_022575.4(VPS16):​c.143-2A>T variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS16 NM_022575.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.56
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3, offset of -35, new splice context is: ttcacatggggtgggcctAGgga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-2860052-A-T is Pathogenic according to our data. Variant chr20-2860052-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2663845.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS16	NM_022575.4	c.143-2A>T		splice_acceptor_variant, intron_variant	Intron 2 of 23	ENST00000380445.8	NP_072097.2
VPS16	NM_080413.3	c.143-2A>T		splice_acceptor_variant, intron_variant	Intron 2 of 19		NP_536338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS16	ENST00000380445.8	c.143-2A>T		splice_acceptor_variant, intron_variant	Intron 2 of 23	1	NM_022575.4	ENSP00000369810.3
VPS16	ENST00000380469.7	c.143-2A>T		splice_acceptor_variant, intron_variant	Intron 2 of 19	2		ENSP00000369836.3
VPS16	ENST00000453689.5	c.15+245A>T		intron_variant	Intron 2 of 9	3		ENSP00000417031.1
VPS16	ENST00000417508.1	c.15+245A>T		intron_variant	Intron 2 of 8	5		ENSP00000409840.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dystonia 30 Pathogenic:1

-

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	0.98
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.6
GERP RS		4.8
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.89		Position offset: 2

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

Other links and lift over

hg19: chr20-2840698;