rs61754113

chr8-99720974-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017890.5(VPS13B):c.7052G>A(p.Arg2351Gln) 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_017890.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.59

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.7052G>A	p.Arg2351Gln	missense_variant	39/62	ENST00000358544.7
VPS13B	NM_152564.5	c.6977G>A	p.Arg2326Gln	missense_variant	39/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.7052G>A	p.Arg2351Gln	missense_variant	39/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.6977G>A	p.Arg2326Gln	missense_variant	39/62	1	NM_152564.5	P1

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

GnomAD3 exomes AF: 0.00146 AC: 366 AN: 251194 Hom.: 1 AF XY: 0.00127 AC XY: 173 AN XY: 135758

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0218

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.00116

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

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.000964 Hom.: 1

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

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 29, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2022	See Variant Classification Assertion Criteria. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Cohen syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.0096	T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.22
Sift	Benign	0.053	T;D
Sift4G	Uncertain	0.051	T;T
Polyphen		0.99	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs61754113; hg19: chr8-100733202;