rs61754113

Variant names:

• chr8-99720974-G-A
• rs61754113
• NM_017890.5:c.7052G>A

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.6977G>A​(p.Arg2326Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00113 in 1,613,914 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (6 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.59
• Publications: 2 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=0.009564519).
• BP6: Variant 8-99720974-G-A is Benign according to our data. Variant chr8-99720974-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00599 (912/152182) while in subpopulation AFR AF = 0.0209 (866/41524). AF 95% confidence interval is 0.0197. There are 13 homozygotes in GnomAd4. There are 439 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.7052G>A	p.Arg2351Gln	missense	Exon 39 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.6977G>A	p.Arg2326Gln	missense	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.7052G>A	p.Arg2351Gln	missense	Exon 39 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.6977G>A	p.Arg2326Gln	missense	Exon 39 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000518569.1	TSL:3	n.107G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00600 AC: 912 AN: 152064 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00146 AC: 366 AN: 251194 AF XY: 0.00127

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000625 AC: 914 AN: 1461732 Hom.: 6 Cov.: 32 AF XY: 0.000539 AC XY: 392 AN XY: 727164

African (AFR) AF: 0.0218 AC: 731 AN: 33470

American (AMR) AF: 0.000984 AC: 44 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111920

Other (OTH) AF: 0.00116 AC: 70 AN: 60386

GnomAD4 genome AF: 0.00599 AC: 912 AN: 152182 Hom.: 13 Cov.: 32 AF XY: 0.00590 AC XY: 439 AN XY: 74388

African (AFR) AF: 0.0209 AC: 866 AN: 41524

American (AMR) AF: 0.00137 AC: 21 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67994

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00228 Hom.: 4

Bravo AF: 0.00680

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00169 AC: 205

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.22
Sift	Benign	0.053	T
Sift4G	Uncertain	0.051	T
Polyphen		0.99	D
Vest4		0.36
MVP		0.78
MPC		0.39
ClinPred		0.012	T
GERP RS		5.2
Varity_R		0.25
gMVP		0.63
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61754113; hg19: chr8-100733202;