rs34513504

Variant names:

• chr8-99848918-G-A
• rs34513504
• NM_017890.5:c.10136+24G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152564.5(VPS13B):​c.10061+24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,591,598 control chromosomes in the GnomAD database, including 27,626 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5089 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22537 hom.)
• Consequence: VPS13B NM_152564.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.26
• Publications: 9 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=-0.93).
• BP6: Variant 8-99848918-G-A is Benign according to our data. Variant chr8-99848918-G-A is described in ClinVar as Benign. ClinVar VariationId is 262652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 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.10136+24G>A		intron	N/A	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.10061+24G>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.10136+24G>A		intron	N/A	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.10061+24G>A		intron	N/A	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.10136+24G>A		intron	N/A	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35057 AN: 151900 Hom.: 5062 Cov.: 32

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.196

GnomAD2 exomes AF: 0.173 AC: 43440 AN: 251094 AF XY: 0.167

Gnomad AFR exome AF: 0.419

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.131

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.170 AC: 245137 AN: 1439580 Hom.: 22537 Cov.: 26 AF XY: 0.168 AC XY: 120579 AN XY: 717576

African (AFR) AF: 0.422 AC: 13957 AN: 33084

American (AMR) AF: 0.157 AC: 7029 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 5357 AN: 26006

East Asian (EAS) AF: 0.122 AC: 4834 AN: 39590

South Asian (SAS) AF: 0.118 AC: 10111 AN: 85770

European-Finnish (FIN) AF: 0.146 AC: 7780 AN: 53346

Middle Eastern (MID) AF: 0.144 AC: 828 AN: 5744

European-Non Finnish (NFE) AF: 0.169 AC: 184701 AN: 1091762

Other (OTH) AF: 0.177 AC: 10540 AN: 59588

GnomAD4 genome AF: 0.231 AC: 35124 AN: 152018 Hom.: 5089 Cov.: 32 AF XY: 0.227 AC XY: 16894 AN XY: 74314

African (AFR) AF: 0.412 AC: 17080 AN: 41458

American (AMR) AF: 0.159 AC: 2424 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 719 AN: 3462

East Asian (EAS) AF: 0.130 AC: 673 AN: 5172

South Asian (SAS) AF: 0.108 AC: 518 AN: 4814

European-Finnish (FIN) AF: 0.157 AC: 1661 AN: 10566

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11447 AN: 67956

Other (OTH) AF: 0.194 AC: 408 AN: 2108

Alfa AF: 0.195 Hom.: 654

Bravo AF: 0.242

Asia WGS AF: 0.159 AC: 554 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cohen syndrome (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.029
DANN	Benign	0.18
PhyloP100		-1.3
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: rs34513504; hg19: chr8-100861146; COSMIC: COSV62132342;