rs181625846

Variant names:

• chr8-99121222-A-G
• rs181625846
• NM_017890.5:c.983A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-99121222-A-G
• chr8-99121222-A-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152564.5(VPS13B):​c.983A>G​(p.His328Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000696 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H328Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (0 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:6 O:1
• Conservation: PhyloP100: 3.64
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018320441).

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.983A>G	p.His328Arg	missense	Exon 8 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.983A>G	p.His328Arg	missense	Exon 8 of 62	NP_689777.3
	VPS13B	NM_015243.3		c.983A>G	p.His328Arg	missense	Exon 8 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.983A>G	p.His328Arg	missense	Exon 8 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.983A>G	p.His328Arg	missense	Exon 8 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000441350.2	TSL:1	c.983A>G	p.His328Arg	missense	Exon 8 of 8	ENSP00000398472.2	Q7Z7G8-5

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000546 AC: 137 AN: 251030 AF XY: 0.000523

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000775

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000712 AC: 1041 AN: 1461766 Hom.: 0 Cov.: 30 AF XY: 0.000694 AC XY: 505 AN XY: 727172

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00101 AC: 45 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000498 AC: 13 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.000832 AC: 925 AN: 1111958

Other (OTH) AF: 0.000729 AC: 44 AN: 60388

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74478

African (AFR) AF: 0.000120 AC: 5 AN: 41558

American (AMR) AF: 0.000653 AC: 10 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000710 Hom.: 0

Bravo AF: 0.000642

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000544 AC: 66

EpiCase AF: 0.000873

EpiControl AF: 0.000949

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	1	Cohen syndrome (7)
-	2	4	not provided (6)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	-	1	VPS13B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.20
Sift	Benign	0.64	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.38
MVP		0.68
MPC		0.15
ClinPred		0.0083	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052
gMVP		0.36
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs181625846; hg19: chr8-100133450;