NM_017890.5:c.11688C>T

Variant names:

• chr8-99871565-C-T
• rs139436386
• NM_017890.5:c.11688C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_017890.5(VPS13B):​c.11688C>T​(p.Phe3896Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00073 in 1,614,214 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00077 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: VPS13B NM_017890.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.211
• Publications: 1 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: ClinGen, Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 8-99871565-C-T is Benign according to our data. Variant chr8-99871565-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95828.
• BP7: Synonymous conserved (PhyloP=0.211 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.11688C>T	p.Phe3896Phe	synonymous	Exon 61 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.11613C>T	p.Phe3871Phe	synonymous	Exon 61 of 62	NP_689777.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.11688C>T	p.Phe3896Phe	synonymous	Exon 61 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.11613C>T	p.Phe3871Phe	synonymous	Exon 61 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000493587.1	TSL:2	n.1190C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000712 AC: 179 AN: 251460 AF XY: 0.000736

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000897

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000726 AC: 1061 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.000704 AC XY: 512 AN XY: 727236

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00150 AC: 67 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53416

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5756

European-Non Finnish (NFE) AF: 0.000824 AC: 916 AN: 1112010

Other (OTH) AF: 0.000844 AC: 51 AN: 60396

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000711 AC XY: 53 AN XY: 74496

African (AFR) AF: 0.000168 AC: 7 AN: 41580

American (AMR) AF: 0.00222 AC: 34 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000594 Hom.: 0

Bravo AF: 0.00106

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Cohen syndrome (4)
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	9.2
DANN	Benign	0.79
PhyloP100		0.21
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs139436386; hg19: chr8-100883793;