rs61753724

Variant names:

• chr8-99720960-A-G
• rs61753724
• NM_017890.5:c.7038A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_152564.5(VPS13B):​c.6963A>G​(p.Val2321Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0467 in 1,613,908 control chromosomes in the GnomAD database, including 2,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (537 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1688 hom.)
• Consequence: VPS13B NM_152564.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.618
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 8-99720960-A-G is Benign according to our data. Variant chr8-99720960-A-G is described in ClinVar as Benign. ClinVar VariationId is 95863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.618 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 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.7038A>G	p.Val2346Val	synonymous	Exon 39 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.6963A>G	p.Val2321Val	synonymous	Exon 39 of 62	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.7038A>G	p.Val2346Val	synonymous	Exon 39 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.6963A>G	p.Val2321Val	synonymous	Exon 39 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000518569.1	TSL:3	n.93A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0686 AC: 10428 AN: 152056 Hom.: 534 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.0566

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0416

Gnomad OTH AF: 0.0580

GnomAD2 exomes AF: 0.0474 AC: 11903 AN: 251248 AF XY: 0.0441

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.0560

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.0633

Gnomad FIN exome AF: 0.0453

Gnomad NFE exome AF: 0.0391

Gnomad OTH exome AF: 0.0390

GnomAD4 exome AF: 0.0444 AC: 64955 AN: 1461734 Hom.: 1688 Cov.: 32 AF XY: 0.0431 AC XY: 31322 AN XY: 727168

African (AFR) AF: 0.141 AC: 4730 AN: 33474

American (AMR) AF: 0.0548 AC: 2450 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 479 AN: 26130

East Asian (EAS) AF: 0.0449 AC: 1783 AN: 39670

South Asian (SAS) AF: 0.0231 AC: 1991 AN: 86254

European-Finnish (FIN) AF: 0.0423 AC: 2259 AN: 53414

Middle Eastern (MID) AF: 0.0198 AC: 114 AN: 5766

European-Non Finnish (NFE) AF: 0.0434 AC: 48307 AN: 1111914

Other (OTH) AF: 0.0471 AC: 2842 AN: 60388

GnomAD4 genome AF: 0.0687 AC: 10457 AN: 152174 Hom.: 537 Cov.: 32 AF XY: 0.0688 AC XY: 5120 AN XY: 74394

African (AFR) AF: 0.139 AC: 5787 AN: 41506

American (AMR) AF: 0.0503 AC: 769 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3464

East Asian (EAS) AF: 0.0565 AC: 293 AN: 5182

South Asian (SAS) AF: 0.0222 AC: 107 AN: 4818

European-Finnish (FIN) AF: 0.0445 AC: 472 AN: 10604

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0416 AC: 2826 AN: 67992

Other (OTH) AF: 0.0569 AC: 120 AN: 2108

Alfa AF: 0.0566 Hom.: 145

Bravo AF: 0.0727

Asia WGS AF: 0.0560 AC: 197 AN: 3476

EpiCase AF: 0.0386

EpiControl AF: 0.0348

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Cohen syndrome (5)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.5
DANN	Benign	0.74
PhyloP100		0.62
Mutation Taster		=97/3	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: rs61753724; hg19: chr8-100733188; COSMIC: COSV62136791;