chr8-99013353-C-G

Variant names:

• chr8-99013353-C-G
• rs147672364
• NM_017890.5:c.-30+6C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152564.5(VPS13B):​c.-30+6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 278,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: VPS13B NM_152564.5 splice_region, intron
• Scores: Splicing: ADA: 0.0002489
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0550
• 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-DT (HGNC:54375): (VPS13B divergent transcript)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13B	NM_017890.5	c.-30+6C>G		splice_region_variant, intron_variant	Intron 1 of 61	ENST00000358544.7	NP_060360.3
VPS13B	NM_152564.5	c.-30+6C>G		splice_region_variant, intron_variant	Intron 1 of 61	ENST00000357162.7	NP_689777.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13B	ENST00000358544.7	c.-30+6C>G		splice_region_variant, intron_variant	Intron 1 of 61	1	NM_017890.5	ENSP00000351346.2
VPS13B	ENST00000357162.7	c.-30+6C>G		splice_region_variant, intron_variant	Intron 1 of 61	1	NM_152564.5	ENSP00000349685.2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000265

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000325 AC: 41 AN: 125968 Hom.: 0 Cov.: 0 AF XY: 0.000249 AC XY: 17 AN XY: 68272

African (AFR) AF: 0.000256 AC: 1 AN: 3910

American (AMR) AF: 0.00 AC: 0 AN: 4686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2834

East Asian (EAS) AF: 0.00 AC: 0 AN: 5464

South Asian (SAS) AF: 0.00 AC: 0 AN: 22472

European-Finnish (FIN) AF: 0.000164 AC: 1 AN: 6104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 464

European-Non Finnish (NFE) AF: 0.000501 AC: 37 AN: 73790

Other (OTH) AF: 0.000320 AC: 2 AN: 6244

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74282

African (AFR) AF: 0.0000725 AC: 3 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000170

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cohen syndrome Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	8.2
DANN	Benign	0.50
PhyloP100		0.055
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.046
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147672364; hg19: chr8-100025581;