8-99099684-A-G

Variant names:

• chr8-99099684-A-G
• rs6468665
• NM_017890.5:c.412+3252A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017890.5(VPS13B):​c.412+3252A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.826 in 152,130 control chromosomes in the GnomAD database, including 52,424 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.83 (52424 hom., cov: 32)
• Consequence: VPS13B NM_017890.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• 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: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.869 is higher than 0.05.

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.412+3252A>G		intron	N/A	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.412+3252A>G		intron	N/A	NP_689777.3
	VPS13B	NM_015243.3		c.412+3252A>G		intron	N/A	NP_056058.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.412+3252A>G		intron	N/A	ENSP00000351346.2
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.412+3252A>G		intron	N/A	ENSP00000349685.2
	VPS13B	ENST00000441350.2	TSL:1	c.412+3252A>G		intron	N/A	ENSP00000398472.2

Frequencies

GnomAD3 genomes AF: 0.826 AC: 125584 AN: 152012 Hom.: 52390 Cov.: 32

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.822

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.844

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.889

Gnomad FIN AF: 0.837

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.801

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.826 AC: 125670 AN: 152130 Hom.: 52424 Cov.: 32 AF XY: 0.823 AC XY: 61237 AN XY: 74384

African (AFR) AF: 0.877 AC: 36420 AN: 41532

American (AMR) AF: 0.671 AC: 10246 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 2930 AN: 3472

East Asian (EAS) AF: 0.622 AC: 3214 AN: 5164

South Asian (SAS) AF: 0.889 AC: 4286 AN: 4822

European-Finnish (FIN) AF: 0.837 AC: 8844 AN: 10564

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.839 AC: 57032 AN: 67978

Other (OTH) AF: 0.802 AC: 1697 AN: 2116

Alfa AF: 0.821 Hom.: 29703

Bravo AF: 0.809

Asia WGS AF: 0.744 AC: 2587 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.28
DANN	Benign	0.34
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6468665; hg19: chr8-100111912;