rs28940272
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_017890.5(VPS13B):āc.8978A>Gā(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: š 0.0038 ( 3 hom., cov: 32)
Exomes š: 0.0051 ( 19 hom. )
Consequence
VPS13B
NM_017890.5 missense
NM_017890.5 missense
Scores
7
5
5
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 | UniProt |
---|---|---|---|---|---|---|---|
VPS13B | NM_017890.5 | c.8978A>G | p.Asn2993Ser | missense_variant | 49/62 | ENST00000358544.7 | |
VPS13B | NM_152564.5 | c.8903A>G | p.Asn2968Ser | missense_variant | 49/62 | ENST00000357162.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VPS13B | ENST00000358544.7 | c.8978A>G | p.Asn2993Ser | missense_variant | 49/62 | 1 | NM_017890.5 | ||
VPS13B | ENST00000357162.7 | c.8903A>G | p.Asn2968Ser | missense_variant | 49/62 | 1 | NM_152564.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00384 AC: 584AN: 152194Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00318 AC: 799AN: 251260Hom.: 1 AF XY: 0.00316 AC XY: 429AN XY: 135784
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GnomAD4 exome AF: 0.00513 AC: 7493AN: 1461726Hom.: 19 Cov.: 32 AF XY: 0.00489 AC XY: 3557AN XY: 727170
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GnomAD4 genome ? AF: 0.00383 AC: 584AN: 152312Hom.: 3 Cov.: 32 AF XY: 0.00318 AC XY: 237AN XY: 74478
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ESP6500AA
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Benign:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cohen syndrome Pathogenic:1Uncertain:1Benign:5
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2004 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 29, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | 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 | - - |
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Oct 29, 2021 | - - |
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 31, 2017 | - - |
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. - |
not provided Benign:3
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) - |
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 - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A;A
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
0.19
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at