8-99481592-C-T

Position:

• chr8-99481592-C-T

Variant summary

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

The NM_152564.5(VPS13B):​c.3667-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,612,754 control chromosomes in the GnomAD database, including 2,228 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (145 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2083 hom.)
• Consequence: VPS13B NM_152564.5 splice_region, intron
• Scores: Splicing: ADA: 0.00007806
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.911

Genes affected

VPS13B (HGNC:2183): (vacuolar protein sorting 13 homolog B) This gene encodes a potential transmembrane protein that may function in vesicle-mediated transport and sorting of proteins within the cell. This protein may play a role in the development and the function of the eye, hematological system, and central nervous system. Mutations in this gene have been associated with Cohen syndrome. Multiple splice variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

VPS13B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-99481592-C-T is Benign according to our data. Variant chr8-99481592-C-T is described in ClinVar as [Benign]. Clinvar id is 95848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99481592-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.3667-7C>T		splice_region_variant, intron_variant		ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.3667-7C>T		splice_region_variant, intron_variant		ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.3667-7C>T		splice_region_variant, intron_variant		1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.3667-7C>T		splice_region_variant, intron_variant		1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5467 AN: 151998 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0506

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0175

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0525

Gnomad OTH AF: 0.0612

GnomAD3 exomes AF: 0.0380 AC: 9517 AN: 250768 Hom.: 273 AF XY: 0.0387 AC XY: 5248 AN XY: 135578

Gnomad AFR exome AF: 0.00815

Gnomad AMR exome AF: 0.0361

Gnomad ASJ exome AF: 0.0643

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0173

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.0553

Gnomad OTH exome AF: 0.0522

GnomAD4 exome AF: 0.0489 AC: 71421 AN: 1460638 Hom.: 2083 Cov.: 31 AF XY: 0.0483 AC XY: 35125 AN XY: 726704

Gnomad4 AFR exome AF: 0.0102

Gnomad4 AMR exome AF: 0.0384

Gnomad4 ASJ exome AF: 0.0649

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0186

Gnomad4 FIN exome AF: 0.0191

Gnomad4 NFE exome AF: 0.0552

Gnomad4 OTH exome AF: 0.0509

GnomAD4 genome AF: 0.0359 AC: 5468 AN: 152116 Hom.: 145 Cov.: 32 AF XY: 0.0344 AC XY: 2555 AN XY: 74342

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.0506

Gnomad4 ASJ AF: 0.0597

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0175

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.0526

Gnomad4 OTH AF: 0.0611

Alfa AF: 0.0494 Hom.: 113

Bravo AF: 0.0389

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.0595

EpiControl AF: 0.0602

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Benign:7

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.6
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000078
dbscSNV1_RF	Benign	0.026
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: rs35543295; hg19: chr8-100493820;