chr8-99717158-A-AT

Variant names:

• chr8-99717158-A-AT
• rs398124337
• NM_017890.5:c.6530-4dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_152564.5(VPS13B):​c.6455-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,564,658 control chromosomes in the GnomAD database, including 272 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (20 hom., cov: 32)
  • Exomes 𝑓: 0.012 (252 hom.)
• Consequence: VPS13B NM_152564.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.735
• 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: ClinGen, Myriad Women’s Health, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-99717158-A-AT is Benign according to our data. Variant chr8-99717158-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.065 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152564.5. 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.6530-4dupT		splice_region intron	N/A	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.6455-4dupT		splice_region intron	N/A	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.6530-13_6530-12insT		intron	N/A	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.6455-13_6455-12insT		intron	N/A	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.6530-13_6530-12insT		intron	N/A	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes AF: 0.00892 AC: 1350 AN: 151324 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00925

Gnomad ASJ AF: 0.00895

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0718

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00885

Gnomad OTH AF: 0.00814

GnomAD2 exomes AF: 0.0153 AC: 3482 AN: 227226 AF XY: 0.0186

Gnomad AFR exome AF: 0.00144

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.00951

Gnomad EAS exome AF: 0.000302

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0123 AC: 17321 AN: 1413216 Hom.: 252 Cov.: 30 AF XY: 0.0138 AC XY: 9747 AN XY: 704632

African (AFR) AF: 0.00180 AC: 58 AN: 32286

American (AMR) AF: 0.00504 AC: 222 AN: 44008

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 257 AN: 25472

East Asian (EAS) AF: 0.000309 AC: 12 AN: 38828

South Asian (SAS) AF: 0.0635 AC: 5395 AN: 85010

European-Finnish (FIN) AF: 0.0140 AC: 735 AN: 52628

Middle Eastern (MID) AF: 0.0183 AC: 103 AN: 5630

European-Non Finnish (NFE) AF: 0.00913 AC: 9773 AN: 1070822

Other (OTH) AF: 0.0131 AC: 766 AN: 58532

GnomAD4 genome AF: 0.00889 AC: 1347 AN: 151442 Hom.: 20 Cov.: 32 AF XY: 0.0103 AC XY: 762 AN XY: 74004

African (AFR) AF: 0.00160 AC: 66 AN: 41296

American (AMR) AF: 0.00924 AC: 140 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.00895 AC: 31 AN: 3464

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

South Asian (SAS) AF: 0.0712 AC: 341 AN: 4788

European-Finnish (FIN) AF: 0.0143 AC: 150 AN: 10492

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00886 AC: 600 AN: 67754

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00509 Hom.: 0

Bravo AF: 0.00652

Asia WGS AF: 0.0310 AC: 109 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cohen syndrome (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism (auto)

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: rs398124337; hg19: chr8-100729386; COSMIC: COSV100662884; COSMIC: COSV100662884;