rs61759485

Variant names:

• chr8-99442576-A-G
• rs61759485
• NM_017890.5:c.3386A>G

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.3386A>G​(p.Lys1129Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00487 in 1,614,004 control chromosomes in the GnomAD database, including 26 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. K1129E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0044 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (25 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 4.76
• 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=0.009524286).
• BP6: Variant 8-99442576-A-G is Benign according to our data. Variant chr8-99442576-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95845.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 = 0.00441 (671/152298) while in subpopulation NFE AF = 0.00613 (417/68020). AF 95% confidence interval is 0.00564. There are 1 homozygotes in GnomAd4. There are 303 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 25 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.3386A>G	p.Lys1129Arg	missense	Exon 23 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.3386A>G	p.Lys1129Arg	missense	Exon 23 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.3386A>G	p.Lys1129Arg	missense	Exon 23 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.3386A>G	p.Lys1129Arg	missense	Exon 23 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000355155.6	TSL:1	n.3383A>G		non_coding_transcript_exon	Exon 23 of 28	ENSP00000347281.2	A0A8C8KE22

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 672 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00613

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00464 AC: 1166 AN: 251224 AF XY: 0.00474

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00434

Gnomad NFE exome AF: 0.00688

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00492 AC: 7197 AN: 1461706 Hom.: 25 Cov.: 31 AF XY: 0.00487 AC XY: 3542 AN XY: 727158

African (AFR) AF: 0.00242 AC: 81 AN: 33474

American (AMR) AF: 0.00347 AC: 155 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00367 AC: 96 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00169 AC: 146 AN: 86256

European-Finnish (FIN) AF: 0.00442 AC: 236 AN: 53416

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00553 AC: 6149 AN: 1111890

Other (OTH) AF: 0.00540 AC: 326 AN: 60390

GnomAD4 genome AF: 0.00441 AC: 671 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00407 AC XY: 303 AN XY: 74476

African (AFR) AF: 0.00315 AC: 131 AN: 41580

American (AMR) AF: 0.00412 AC: 63 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4822

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00613 AC: 417 AN: 68020

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00544 Hom.: 9

Bravo AF: 0.00459

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00518 AC: 629

EpiCase AF: 0.00485

EpiControl AF: 0.00640

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.13
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.28
MPC		0.099
ClinPred		0.041	T
GERP RS		3.3
Varity_R		0.069
gMVP		0.43
Mutation Taster		=99/1	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: rs61759485; hg19: chr8-100454804;