chr8-99766979-T-C

Variant names:

• chr8-99766979-T-C
• rs545008110
• NM_017890.5:c.7322+9T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_017890.5(VPS13B):​c.7322+9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,612,826 control chromosomes in the GnomAD database, including 1 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 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000030 (1 hom.)
• Consequence: VPS13B NM_017890.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.883
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 8-99766979-T-C is Benign according to our data. Variant chr8-99766979-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437239.

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.7322+9T>C		intron	N/A	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.7247+9T>C		intron	N/A	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.7322+9T>C		intron	N/A	ENSP00000351346.2
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.7247+9T>C		intron	N/A	ENSP00000349685.2
	VPS13B	ENST00000518569.1	TSL:3	n.377+9T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152168 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000559 AC: 14 AN: 250640 AF XY: 0.0000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460540 Hom.: 1 Cov.: 30 AF XY: 0.0000482 AC XY: 35 AN XY: 726702

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39580

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111122

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152286 Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6 AN XY: 74442

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

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: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Cohen syndrome (2)
-	1	-	not specified (1)
-	-	1	VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.9
DANN	Benign	0.78
PhyloP100		-0.88

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: rs545008110; hg19: chr8-100779207;