rs61753721

Variant names:

• chr8-99193027-G-A
• rs61753721
• NM_017890.5:c.2485G>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.2485G>A​(p.Ala829Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,582 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (8 hom., cov: 32)
  • Exomes 𝑓: 0.011 (121 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 2.94
• Publications: 10 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=0.006864518).
• BP6: Variant 8-99193027-G-A is Benign according to our data. Variant chr8-99193027-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95839.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 = 0.00823 (1253/152230) while in subpopulation NFE AF = 0.0126 (858/67986). AF 95% confidence interval is 0.0119. There are 8 homozygotes in GnomAd4. There are 597 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.2485G>A	p.Ala829Thr	missense	Exon 17 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.2485G>A	p.Ala829Thr	missense	Exon 17 of 62	NP_689777.3
	VPS13B	NM_015243.3		c.2485G>A	p.Ala829Thr	missense	Exon 17 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.2485G>A	p.Ala829Thr	missense	Exon 17 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.2485G>A	p.Ala829Thr	missense	Exon 17 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000355155.6	TSL:1	n.2485G>A		non_coding_transcript_exon	Exon 17 of 28	ENSP00000347281.2	A0A8C8KE22

Frequencies

GnomAD3 genomes AF: 0.00824 AC: 1254 AN: 152112 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00867 AC: 2178 AN: 251160 AF XY: 0.00883

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00969

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00553

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0114 AC: 16593 AN: 1461352 Hom.: 121 Cov.: 31 AF XY: 0.0111 AC XY: 8089 AN XY: 726980

African (AFR) AF: 0.00158 AC: 53 AN: 33466

American (AMR) AF: 0.00970 AC: 434 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 273 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39614

South Asian (SAS) AF: 0.00526 AC: 454 AN: 86240

European-Finnish (FIN) AF: 0.00513 AC: 273 AN: 53268

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5762

European-Non Finnish (NFE) AF: 0.0130 AC: 14430 AN: 1111788

Other (OTH) AF: 0.0109 AC: 656 AN: 60376

GnomAD4 genome AF: 0.00823 AC: 1253 AN: 152230 Hom.: 8 Cov.: 32 AF XY: 0.00802 AC XY: 597 AN XY: 74428

African (AFR) AF: 0.00207 AC: 86 AN: 41554

American (AMR) AF: 0.0118 AC: 181 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4824

European-Finnish (FIN) AF: 0.00500 AC: 53 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0126 AC: 858 AN: 67986

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.0105 Hom.: 27

Bravo AF: 0.00822

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.00857 AC: 1040

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0123

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (8)
-	-	4	not specified (4)
-	-	3	Cohen syndrome (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.12
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.9
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.14
Sift	Benign	0.75	T
Sift4G	Uncertain	0.060	T
Polyphen		0.62	P
Vest4		0.19
MVP		0.68
MPC		0.12
ClinPred		0.021	T
GERP RS		3.9
Varity_R		0.11
gMVP		0.25
Mutation Taster		=89/11	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: rs61753721; hg19: chr8-100205255; COSMIC: COSV99050300;