NM_017890.5:c.2275G>C

Variant names:

• chr8-99170105-G-C
• rs140848350
• NM_017890.5:c.2275G>C

Variant summary

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

The NM_017890.5(VPS13B):​c.2275G>C​(p.Val759Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,612,966 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (152 hom.)
• Consequence: VPS13B NM_017890.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.10
• Publications: 6 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 8-99170105-G-C is Benign according to our data. Variant chr8-99170105-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0679 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017890.5. 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.2275G>C	p.Val759Leu	missense	Exon 16 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.2275G>C	p.Val759Leu	missense	Exon 16 of 62	NP_689777.3
	VPS13B	NM_015243.3		c.2275G>C	p.Val759Leu	missense	Exon 16 of 18	NP_056058.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.2275G>C	p.Val759Leu	missense	Exon 16 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.2275G>C	p.Val759Leu	missense	Exon 16 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000355155.6	TSL:1	n.2275G>C		non_coding_transcript_exon	Exon 16 of 28	ENSP00000347281.2	A0A8C8KE22

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 510 AN: 151972 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0296

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.0109 AC: 2746 AN: 251258 AF XY: 0.00786

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.0775

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00225 AC: 3281 AN: 1460876 Hom.: 152 Cov.: 31 AF XY: 0.00180 AC XY: 1309 AN XY: 726772

African (AFR) AF: 0.000628 AC: 21 AN: 33456

American (AMR) AF: 0.0699 AC: 3124 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39646

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111226

Other (OTH) AF: 0.00128 AC: 77 AN: 60358

GnomAD4 genome AF: 0.00337 AC: 512 AN: 152090 Hom.: 17 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74354

African (AFR) AF: 0.00101 AC: 42 AN: 41538

American (AMR) AF: 0.0297 AC: 453 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67878

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00687

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00809 AC: 982

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Cohen syndrome (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.040
Sift	Benign	0.29	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.13
MPC		0.12
ClinPred		0.000039	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.34
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140848350; hg19: chr8-100182333;