rs797046093

Variant names:

• chr8-99868348-C-G
• rs797046093
• NM_017890.5:c.11350C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-99868348-C-G
• chr8-99868348-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017890.5(VPS13B):​c.11350C>G​(p.Gln3784Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.64
• Publications: 0 publications found

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]

VPS13B Gene-Disease associations (from GenCC):

• Cohen syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1784963).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017890.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.11350C>G	p.Gln3784Glu	missense	Exon 59 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.11275C>G	p.Gln3759Glu	missense	Exon 59 of 62	NP_689777.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.11350C>G	p.Gln3784Glu	missense	Exon 59 of 62	ENSP00000351346.2
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.11275C>G	p.Gln3759Glu	missense	Exon 59 of 62	ENSP00000349685.2
	VPS13B	ENST00000493587.1	TSL:2	n.292C>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461890 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cohen syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.093
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.6
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.082
Sift	Benign	0.26	T
Sift4G	Benign	0.38	T
Polyphen		0.0040	B
Vest4		0.34
MutPred		0.28		Loss of loop (P = 0.0512)
MVP		0.72
MPC		0.15
ClinPred		0.81	D
GERP RS		5.8
Varity_R		0.13
gMVP		0.64
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs797046093; hg19: chr8-100880576;