rs111751379

chr8-99778930-G-A

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.7753G>A(p.Glu2585Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,613,934 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (23 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 3.37

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=0.0072244406).
• BP6: Variant 8-99778930-G-A is Benign according to our data. Variant chr8-99778930-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-99778930-G-A is described in Lovd as [Likely_benign]. Variant chr8-99778930-G-A is described in Lovd as [Likely_pathogenic].
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.7753G>A	p.Glu2585Lys	missense_variant	42/62	ENST00000358544.7
VPS13B	NM_152564.5	c.7678G>A	p.Glu2560Lys	missense_variant	42/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.7753G>A	p.Glu2585Lys	missense_variant	42/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.7678G>A	p.Glu2560Lys	missense_variant	42/62	1	NM_152564.5	P1

Frequencies

GnomAD3 genomes AF: 0.00305 AC: 464 AN: 152162 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00501

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00326 AC: 818 AN: 250916 Hom.: 3 AF XY: 0.00330 AC XY: 447 AN XY: 135596

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00546

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00464 AC: 6789 AN: 1461654 Hom.: 23 Cov.: 32 AF XY: 0.00471 AC XY: 3426 AN XY: 727126

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00184

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.00551

Gnomad4 OTH exome AF: 0.00440

GnomAD4 genome AF: 0.00305 AC: 464 AN: 152280 Hom.: 4 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74462

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00501

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00420 Hom.: 0

Bravo AF: 0.00372

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00322 AC: 391

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00646

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 09, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 28, 2023	The p.Glu2585Lys variant in VPS13B is classified as likely benign because it has been identified in 0.5% (341/68030) of European chromosomes by gnomAD including 4 homozygotes (http://gnomad.broadinstitute.org, v.3.1.2), which is higher than the expected frequency of a disease cuasing variant in this gene. In addition, computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2023	Variant summary: VPS13B c.7753G>A (p.Glu2585Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0033 in 250916 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is higher than 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. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic n=1, VUS n=1, benign/likely benign n=9). Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 11, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	VPS13B: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 11, 2017	- -

Cohen syndrome Benign:6

Benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Dec 04, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 0.5105% (rs111751379, 680/128770 alleles, 3 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 20, 2019	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2019

This alteration is classified as likely 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. -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

research

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.15
Sift	Benign	0.43	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.034	B;B
Vest4		0.28
MVP		0.58
MPC		0.14
ClinPred		0.011	T
GERP RS		3.8
Varity_R		0.061
gMVP		0.34

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: rs111751379; hg19: chr8-100791158; COSMIC: COSV105256656; COSMIC: COSV105256656;