chr8-99823988-T-A

Variant names:

• chr8-99823988-T-A
• rs75904081
• NM_017890.5:c.9405+10T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152564.5(VPS13B):​c.9330+10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 1,610,672 control chromosomes in the GnomAD database, including 525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (27 hom., cov: 32)
  • Exomes 𝑓: 0.024 (498 hom.)
• Consequence: VPS13B NM_152564.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0140
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-99823988-T-A is Benign according to our data. Variant chr8-99823988-T-A is described in ClinVar as Benign. ClinVar VariationId is 130728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0144 (2192/152238) while in subpopulation NFE AF = 0.0255 (1734/68010). AF 95% confidence interval is 0.0245. There are 27 homozygotes in GnomAd4. There are 996 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

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.9405+10T>A		intron	N/A	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.9330+10T>A		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.9405+10T>A		intron	N/A	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.9330+10T>A		intron	N/A	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.9405+10T>A		intron	N/A	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2192 AN: 152120 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00423

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0139 AC: 3440 AN: 248254 AF XY: 0.0141

Gnomad AFR exome AF: 0.00493

Gnomad AMR exome AF: 0.00564

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00794

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0243 AC: 35487 AN: 1458434 Hom.: 498 Cov.: 31 AF XY: 0.0237 AC XY: 17198 AN XY: 725712

African (AFR) AF: 0.00389 AC: 130 AN: 33444

American (AMR) AF: 0.00559 AC: 250 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 286 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00303 AC: 261 AN: 86230

European-Finnish (FIN) AF: 0.00801 AC: 407 AN: 50788

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5752

European-Non Finnish (NFE) AF: 0.0297 AC: 32991 AN: 1111480

Other (OTH) AF: 0.0191 AC: 1151 AN: 60328

GnomAD4 genome AF: 0.0144 AC: 2192 AN: 152238 Hom.: 27 Cov.: 32 AF XY: 0.0134 AC XY: 996 AN XY: 74426

African (AFR) AF: 0.00421 AC: 175 AN: 41542

American (AMR) AF: 0.00628 AC: 96 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4818

European-Finnish (FIN) AF: 0.00754 AC: 80 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0255 AC: 1734 AN: 68010

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0179 Hom.: 9

Bravo AF: 0.0144

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Cohen syndrome (5)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.1
DANN	Benign	0.54
PhyloP100		-0.014
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75904081; hg19: chr8-100836216;