rs138667007

Variant names:

• chr8-99861912-A-G
• rs138667007
• NM_017890.5:c.11256A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_152564.5(VPS13B):​c.11181A>G​(p.Arg3727Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,597,528 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (8 hom.)
• Consequence: VPS13B NM_152564.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.75
• 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 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 8-99861912-A-G is Benign according to our data. Variant chr8-99861912-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 283557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00729 (1107/151930) while in subpopulation AFR AF = 0.0257 (1064/41426). AF 95% confidence interval is 0.0244. There are 9 homozygotes in GnomAd4. There are 514 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.11256A>G	p.Arg3752Arg	synonymous	Exon 58 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.11181A>G	p.Arg3727Arg	synonymous	Exon 58 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.11256A>G	p.Arg3752Arg	synonymous	Exon 58 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.11181A>G	p.Arg3727Arg	synonymous	Exon 58 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.*350A>G		non_coding_transcript_exon	Exon 59 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes AF: 0.00725 AC: 1101 AN: 151812 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

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: 0.0000294

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00172 AC: 374 AN: 217604 AF XY: 0.00122

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.00118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000555

GnomAD4 exome AF: 0.000709 AC: 1025 AN: 1445598 Hom.: 8 Cov.: 32 AF XY: 0.000590 AC XY: 423 AN XY: 717356

African (AFR) AF: 0.0257 AC: 856 AN: 33320

American (AMR) AF: 0.00111 AC: 47 AN: 42328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25692

East Asian (EAS) AF: 0.00 AC: 0 AN: 39058

South Asian (SAS) AF: 0.0000960 AC: 8 AN: 83326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51318

Middle Eastern (MID) AF: 0.000702 AC: 4 AN: 5694

European-Non Finnish (NFE) AF: 0.0000136 AC: 15 AN: 1105124

Other (OTH) AF: 0.00159 AC: 95 AN: 59738

GnomAD4 genome AF: 0.00729 AC: 1107 AN: 151930 Hom.: 9 Cov.: 33 AF XY: 0.00692 AC XY: 514 AN XY: 74266

African (AFR) AF: 0.0257 AC: 1064 AN: 41426

American (AMR) AF: 0.00229 AC: 35 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67952

Other (OTH) AF: 0.00238 AC: 5 AN: 2104

Alfa AF: 0.00378 Hom.: 8

Bravo AF: 0.00839

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cohen syndrome (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.077
DANN	Benign	0.72
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs138667007; hg19: chr8-100874140;