chr8-99431657-C-T

Variant names:

• chr8-99431657-C-T
• rs61753722
• NM_017890.5:c.3203C>T

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.3203C>T​(p.Thr1068Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00933 in 1,611,946 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts 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. T1068P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0079 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (139 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 7.00
• Publications: 14 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=0.006599039).
• BP6: Variant 8-99431657-C-T is Benign according to our data. Variant chr8-99431657-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0079 (1203/152260) while in subpopulation SAS AF = 0.0369 (178/4826). AF 95% confidence interval is 0.0325. There are 11 homozygotes in GnomAd4. There are 633 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.3203C>T	p.Thr1068Ile	missense	Exon 22 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.3203C>T	p.Thr1068Ile	missense	Exon 22 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.3203C>T	p.Thr1068Ile	missense	Exon 22 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.3203C>T	p.Thr1068Ile	missense	Exon 22 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000355155.6	TSL:1	n.3200C>T		non_coding_transcript_exon	Exon 22 of 28	ENSP00000347281.2	A0A8C8KE22

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 1204 AN: 152142 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00976

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0373

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00894

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0105 AC: 2621 AN: 249926 AF XY: 0.0122

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.00855

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.00910

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.00948 AC: 13841 AN: 1459686 Hom.: 139 Cov.: 31 AF XY: 0.0103 AC XY: 7503 AN XY: 726188

African (AFR) AF: 0.00114 AC: 38 AN: 33438

American (AMR) AF: 0.00475 AC: 212 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00943 AC: 246 AN: 26086

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39512

South Asian (SAS) AF: 0.0343 AC: 2958 AN: 86114

European-Finnish (FIN) AF: 0.0137 AC: 726 AN: 53128

Middle Eastern (MID) AF: 0.0169 AC: 97 AN: 5754

European-Non Finnish (NFE) AF: 0.00804 AC: 8930 AN: 1110690

Other (OTH) AF: 0.0105 AC: 632 AN: 60286

GnomAD4 genome AF: 0.00790 AC: 1203 AN: 152260 Hom.: 11 Cov.: 32 AF XY: 0.00850 AC XY: 633 AN XY: 74432

African (AFR) AF: 0.00154 AC: 64 AN: 41572

American (AMR) AF: 0.00975 AC: 149 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0369 AC: 178 AN: 4826

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00896 AC: 609 AN: 68000

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00854 Hom.: 10

Bravo AF: 0.00650

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.0107 AC: 1298

Asia WGS AF: 0.0130 AC: 46 AN: 3476

EpiCase AF: 0.00955

EpiControl AF: 0.00990

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	Cohen syndrome (4)
-	-	4	not specified (4)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	L
PhyloP100		7.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.13
Sift	Benign	0.51	T
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.86
MPC		0.42
ClinPred		0.022	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.68
Mutation Taster		=41/59	disease causing

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: rs61753722; hg19: chr8-100443885;