8-99832630-C-T

Variant names:

• chr8-99832630-C-T
• rs149842139
• NM_017890.5:c.9667C>T

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.9592C>T​(p.Arg3198Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00422 in 1,613,648 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3198Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0043 (16 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.232
• Publications: 11 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 (MetaRNN=0.008605391).
• BP6: Variant 8-99832630-C-T is Benign according to our data. Variant chr8-99832630-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95876.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 = 0.00353 (537/152092) while in subpopulation NFE AF = 0.00606 (412/67994). AF 95% confidence interval is 0.00558. There are 2 homozygotes in GnomAd4. There are 257 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.9667C>T	p.Arg3223Trp	missense	Exon 52 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.9592C>T	p.Arg3198Trp	missense	Exon 52 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.9667C>T	p.Arg3223Trp	missense	Exon 52 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.9592C>T	p.Arg3198Trp	missense	Exon 52 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.9667C>T		non_coding_transcript_exon	Exon 52 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 537 AN: 151974 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00171

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00606

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00361 AC: 906 AN: 250822 AF XY: 0.00366

Gnomad AFR exome AF: 0.000556

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00656

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00619

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00429 AC: 6272 AN: 1461556 Hom.: 16 Cov.: 34 AF XY: 0.00429 AC XY: 3120 AN XY: 727068

African (AFR) AF: 0.000807 AC: 27 AN: 33476

American (AMR) AF: 0.00107 AC: 48 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00650 AC: 170 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39692

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86236

European-Finnish (FIN) AF: 0.00275 AC: 147 AN: 53406

Middle Eastern (MID) AF: 0.000542 AC: 3 AN: 5536

European-Non Finnish (NFE) AF: 0.00506 AC: 5627 AN: 1111982

Other (OTH) AF: 0.00338 AC: 204 AN: 60370

GnomAD4 genome AF: 0.00353 AC: 537 AN: 152092 Hom.: 2 Cov.: 31 AF XY: 0.00346 AC XY: 257 AN XY: 74322

African (AFR) AF: 0.000747 AC: 31 AN: 41500

American (AMR) AF: 0.00295 AC: 45 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00171 AC: 18 AN: 10554

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

European-Non Finnish (NFE) AF: 0.00606 AC: 412 AN: 67994

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00412 Hom.: 9

Bravo AF: 0.00322

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00395 AC: 480

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Cohen syndrome (6)
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.23
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.22
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.021	D
Polyphen		0.98	D
Vest4		0.55
MVP		0.61
MPC		0.41
ClinPred		0.014	T
GERP RS		1.8
Varity_R		0.071
gMVP		0.53
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149842139; hg19: chr8-100844858; COSMIC: COSV62154998;