chr8-99720414-G-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000357162.7(VPS13B):c.6727G>T(p.Glu2243Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000044 ( 0 hom. )
Consequence
VPS13B
ENST00000357162.7 stop_gained
ENST00000357162.7 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: 0.566
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-99720414-G-T is Pathogenic according to our data. Variant chr8-99720414-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| VPS13B | NM_017890.5 | c.6802G>T | p.Glu2268Ter | stop_gained | 38/62 | ENST00000358544.7 | NP_060360.3 | |
| VPS13B | NM_152564.5 | c.6727G>T | p.Glu2243Ter | stop_gained | 38/62 | ENST00000357162.7 | NP_689777.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| VPS13B | ENST00000358544.7 | c.6802G>T | p.Glu2268Ter | stop_gained | 38/62 | 1 | NM_017890.5 | ENSP00000351346 | ||
| VPS13B | ENST00000357162.7 | c.6727G>T | p.Glu2243Ter | stop_gained | 38/62 | 1 | NM_152564.5 | ENSP00000349685 | P1 |
Frequencies
GnomAD3 genomes 0.0000526 AC: 8AN: 152148Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000558 AC: 14AN: 251116Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135742
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GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461690Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 727156
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GnomAD4 genome 0.0000526 AC: 8AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74324
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cohen syndrome Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 12, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 14, 2023 | This sequence change creates a premature translational stop signal (p.Glu2268*) in the VPS13B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VPS13B are known to be pathogenic (PMID: 15141358, 16648375, 20461111). This variant is present in population databases (rs146960401, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with VPS13B-related conditions. ClinVar contains an entry for this variant (Variation ID: 279780). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The heterozygous p.Glu2268Ter variant in VPS13B was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 280580), in one individual with Cohen syndrome. Trio exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 280580). The p.Glu2268Ter variant in VPS13B has been previously reported in one individual with Cohen syndrome (PMID: 25326635) but has been identified in 0.03% (3/10360) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs146960401). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 279780) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This nonsense variant leads to a premature termination codon at position 2268, which is predicted to lead to a truncated or absent protein. Loss of function of the VPS13B gene is an established disease mechanism in autosomal recessive Cohen syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Cohen syndrome. ACMG/AMP Criteria applied: PVS1, PM3 (Richards 2015). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Cohen syndrome (MIM#216550). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (16 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic or pathogenic by multiple clinical laboratories in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This nonsense variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory In trans with a missense variant (L2642P) in a 5-year-old female with global delays, autistic features, short stature, microcephaly, dysmorphic features, hypotonia, joint laxity, scoliosis. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 02, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 19, 2022 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 26, 2022 | Observed as heterozygous in a cohort of individuals undergoing whole genome sequencing with deep phenotyping, but clinical information was not included (Hou et al., 2020); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27535533, 31980526) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 12, 2021 | PVS1, PM2 - |
VPS13B-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 03, 2024 | The VPS13B c.6727G>T variant is predicted to result in premature protein termination (p.Glu2243*). This variant is also known as c.6802G>T, (p.Glu2268*) in an alternate transcript (NM_017890.4). This variant has been documented in a prospective cohort of individuals undergoing whole-genome sequencing, comprehensive metabolomics, and advanced imaging (Supplementary Dataset 1 in Hou. 2020. PubMed ID: 31980526). This variant is reported in 0.029% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Nonsense variants in VPS13B are expected to be pathogenic. Based on this evidence, we interpret this variant as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;N
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at