20-2840955-C-T

Position:

• chr20-2840955-C-T

Variant summary

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

The NM_022575.4(VPS16):​c.53+128C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 907,542 control chromosomes in the GnomAD database, including 14,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5352 hom., cov: 32)
  • Exomes 𝑓: 0.14 (9113 hom.)
• Consequence: VPS16 NM_022575.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.567

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]

PCED1A (HGNC:16212): (PC-esterase domain containing 1A) The protein encoded by this gene is a member of the GDSL/SGNH superfamily. Members of this family are hydrolytic enzymes with esterase and lipase activity and broad substrate specificity. This protein belongs to the Pmr5-Cas1p-esterase subfamily in that it contains the catalytic triad comprised of serine, aspartate and histidine and lacks two conserved regions (glycine after strand S2 and GxND motif). A pseudogene of this gene has been identified on the long arm of chromosome 2. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Sep 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-2840955-C-T is Benign according to our data. Variant chr20-2840955-C-T is described in ClinVar as [Benign]. Clinvar id is 1286534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS16	NM_022575.4	c.53+128C>T		intron_variant		ENST00000380445.8	NP_072097.2
PCED1A	NM_001271168.2	c.-111G>A		5_prime_UTR_variant	1/8		NP_001258097.1
PCED1A	XM_005260804.3	c.-111G>A		5_prime_UTR_variant	1/8		XP_005260861.1
VPS16	NM_080413.3	c.53+128C>T		intron_variant			NP_536338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS16	ENST00000380445.8	c.53+128C>T		intron_variant		1	NM_022575.4	ENSP00000369810	P1

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34080 AN: 152028 Hom.: 5348 Cov.: 32

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0864

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.143 AC: 108374 AN: 755402 Hom.: 9113 Cov.: 10 AF XY: 0.140 AC XY: 53922 AN XY: 383930

Gnomad4 AFR exome AF: 0.454

Gnomad4 AMR exome AF: 0.216

Gnomad4 ASJ exome AF: 0.0754

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.224 AC: 34108 AN: 152140 Hom.: 5352 Cov.: 32 AF XY: 0.221 AC XY: 16445 AN XY: 74394

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.0864

Gnomad4 EAS AF: 0.129

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.174

Alfa AF: 0.181 Hom.: 675

Bravo AF: 0.239

Asia WGS AF: 0.116 AC: 402 AN: 3476

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.0
DANN	Benign	0.84

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: rs2297047; hg19: chr20-2821601;