rs28940272

Positions:

• chr8-99820031-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_017890.5(VPS13B):​c.8978A>G​(p.Asn2993Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,614,038 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (19 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:12
• Conservation: PhyloP100: 7.26

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028394192).
• BP6: Variant 8-99820031-A-G is Benign according to our data. Variant chr8-99820031-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2821.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Benign=1, Uncertain_significance=1}. Variant chr8-99820031-A-G is described in Lovd as [Likely_pathogenic]. Variant chr8-99820031-A-G is described in Lovd as [Pathogenic].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.8978A>G	p.Asn2993Ser	missense_variant	49/62	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.8903A>G	p.Asn2968Ser	missense_variant	49/62	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.8978A>G	p.Asn2993Ser	missense_variant	49/62	1	NM_017890.5	ENSP00000351346
VPS13B	ENST00000357162.7	c.8903A>G	p.Asn2968Ser	missense_variant	49/62	1	NM_152564.5	ENSP00000349685	P1

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 584 AN: 152194 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00557

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00318 AC: 799 AN: 251260 Hom.: 1 AF XY: 0.00316 AC XY: 429 AN XY: 135784

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00493

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00513 AC: 7493 AN: 1461726 Hom.: 19 Cov.: 32 AF XY: 0.00489 AC XY: 3557 AN XY: 727170

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00385

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00612

Gnomad4 OTH exome AF: 0.00475

GnomAD4 genome AF: 0.00383 AC: 584 AN: 152312 Hom.: 3 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74478

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00557

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00484 Hom.: 3

Bravo AF: 0.00449

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00325 AC: 394

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00498

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cohen syndrome Pathogenic:1 Uncertain:1 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 23, 2022	This variant has been reported in the homozygous state in one individual with Cohen syndrome, segregating with disease in 1 affected family member (Kolehmainen 2004 PMID:15141358). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.6% [379/68018], and in 4 homozygotes; https://gnomad.broadinstitute.org/variant/8-99820031-A-G?dataset=gnomad_r3), and in ClinVar, with several laboratories classifying it as benign or likely benign (Variation ID:2821). In an vitro binding assay suggests that this variant may slightly reduce the protein's binding ability (Dziurdzik 2020 PMID:31943017); however, these studies may not accurately represent in vivo biological function. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 29, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2004	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 25, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2022	Variant summary: VPS13B c.8978A>G (p.Asn2993Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 251260 control chromosomes, predominantly at a frequency of 0.0049 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.96 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. c.8978A>G has been reported in the literature in individuals affected with Cohen Syndrome, including a sibling pair who were homozygous for the variant (Kolehmainen_2004), as well as patients with retinal dystrophies including one case with an alternative explanation for disease (Tiwari_2016, Zenteno_2019). These reports do not provide unequivocal conclusions about association of the variant with Cohen Syndrome. At least one publication reports experimental, yeast-based evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Dziurdzik_2020). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Nine submitters classified the variant as likely benign/benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 31, 2017	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	VPS13B: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2020	This variant is associated with the following publications: (PMID: 26764160, 31943017, 15141358, 31736247) -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2023

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.028	T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.1	.;L
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.77
MVP		0.87
MPC		0.19
ClinPred		0.051	T
GERP RS		6.1
Varity_R		0.70
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28940272; hg19: chr8-100832259; COSMIC: COSV62142140;