8-99853608-G-A

Variant names:

• chr8-99853608-G-A
• rs6468694
• NM_017890.5:c.10294G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152564.5(VPS13B):​c.10219G>A​(p.Gly3407Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,614,062 control chromosomes in the GnomAD database, including 12,684 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. G3407E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1118 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11566 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 1.06
• Publications: 32 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=0.0019465387).
• BP6: Variant 8-99853608-G-A is Benign according to our data. Variant chr8-99853608-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

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.10294G>A	p.Gly3432Arg	missense	Exon 56 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.10219G>A	p.Gly3407Arg	missense	Exon 56 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.10294G>A	p.Gly3432Arg	missense	Exon 56 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.10219G>A	p.Gly3407Arg	missense	Exon 56 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.10294G>A		non_coding_transcript_exon	Exon 56 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17990 AN: 152064 Hom.: 1119 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0873

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.123 AC: 31009 AN: 251454 AF XY: 0.123

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.135

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.117

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.124 AC: 180685 AN: 1461880 Hom.: 11566 Cov.: 33 AF XY: 0.123 AC XY: 89725 AN XY: 727244

African (AFR) AF: 0.109 AC: 3633 AN: 33480

American (AMR) AF: 0.130 AC: 5830 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4469 AN: 26136

East Asian (EAS) AF: 0.101 AC: 4021 AN: 39700

South Asian (SAS) AF: 0.0982 AC: 8471 AN: 86254

European-Finnish (FIN) AF: 0.103 AC: 5507 AN: 53418

Middle Eastern (MID) AF: 0.117 AC: 673 AN: 5768

European-Non Finnish (NFE) AF: 0.127 AC: 140743 AN: 1112008

Other (OTH) AF: 0.122 AC: 7338 AN: 60394

GnomAD4 genome AF: 0.118 AC: 17993 AN: 152182 Hom.: 1118 Cov.: 32 AF XY: 0.117 AC XY: 8678 AN XY: 74400

African (AFR) AF: 0.106 AC: 4403 AN: 41514

American (AMR) AF: 0.109 AC: 1673 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 567 AN: 3472

East Asian (EAS) AF: 0.112 AC: 578 AN: 5174

South Asian (SAS) AF: 0.0873 AC: 421 AN: 4820

European-Finnish (FIN) AF: 0.112 AC: 1183 AN: 10600

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8771 AN: 67998

Other (OTH) AF: 0.112 AC: 235 AN: 2104

Alfa AF: 0.128 Hom.: 5868

Bravo AF: 0.122

TwinsUK AF: 0.135 AC: 500

ALSPAC AF: 0.124 AC: 477

ESP6500AA AF: 0.108 AC: 474

ESP6500EA AF: 0.126 AC: 1082

ExAC AF: 0.123 AC: 14944

Asia WGS AF: 0.110 AC: 382 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.134

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Cohen syndrome (7)
-	-	5	not specified (5)
-	-	2	not provided (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.29
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.1
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.055
Sift	Benign	0.53	T
Sift4G	Benign	0.40	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.30		Loss of relative solvent accessibility (P = 0.0676)
MPC		0.15
ClinPred		0.00090	T
GERP RS		2.4
Varity_R		0.027
gMVP		0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs6468694; hg19: chr8-100865836; COSMIC: COSV62142164;