8-99832630-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017890.5(VPS13B):c.9667C>T(p.Arg3223Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 1,613,648 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3223Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0043 (16 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.232

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008605391).
• BP6: Variant 8-99832630-C-T is Benign according to our data. Variant chr8-99832630-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 95876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99832630-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.9667C>T	p.Arg3223Trp	missense_variant	52/62	ENST00000358544.7
VPS13B	NM_152564.5	c.9592C>T	p.Arg3198Trp	missense_variant	52/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.9667C>T	p.Arg3223Trp	missense_variant	52/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.9592C>T	p.Arg3198Trp	missense_variant	52/62	1	NM_152564.5	P1

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 537 AN: 151974 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00171

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00606

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00361 AC: 906 AN: 250822 Hom.: 3 AF XY: 0.00366 AC XY: 497 AN XY: 135626

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00656

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.000556

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00619

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00429 AC: 6272 AN: 1461556 Hom.: 16 Cov.: 34 AF XY: 0.00429 AC XY: 3120 AN XY: 727068

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00650

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00275

Gnomad4 NFE exome AF: 0.00506

Gnomad4 OTH exome AF: 0.00338

GnomAD4 genome AF: 0.00353 AC: 537 AN: 152092 Hom.: 2 Cov.: 31 AF XY: 0.00346 AC XY: 257 AN XY: 74322

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.00295

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00171

Gnomad4 NFE AF: 0.00606

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00478 Hom.: 6

Bravo AF: 0.00322

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00395 AC: 480

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cohen syndrome Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 08, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 18, 2019	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 27, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2020	This variant is associated with the following publications: (PMID: 25502226, 29706646) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	VPS13B: BP4, BS2 -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 04, 2022	Variant summary: VPS13B c.9667C>T (p.Arg3223Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0036 in 250822 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.44 fold of the estimated maximal expected allele frequency for a pathogenic variant in VPS13B causing Cohen Syndrome phenotype (0.0025), strongly suggesting that the variant is benign. To our knowledge, no penetrant association of c.9667C>T in individuals affected with Cohen Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2013	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

VPS13B-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.98	D;D
Vest4		0.55
MVP		0.61
MPC		0.41
ClinPred		0.014	T
GERP RS		1.8
Varity_R		0.071
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149842139; hg19: chr8-100844858; COSMIC: COSV62154998;