rs138127778

Variant names:

• chr8-99848882-C-T
• rs138127778
• NM_017890.5:c.10124C>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.10049C>T​(p.Thr3350Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00855 in 1,613,934 control chromosomes in the GnomAD database, including 72 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T3350T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0066 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (66 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.02
• Publications: 11 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=0.004468918).
• BP6: Variant 8-99848882-C-T is Benign according to our data. Variant chr8-99848882-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130717.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 = 0.00663 (1010/152322) while in subpopulation SAS AF = 0.00973 (47/4828). AF 95% confidence interval is 0.00904. There are 6 homozygotes in GnomAd4. There are 497 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.10124C>T	p.Thr3375Ile	missense	Exon 55 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.10049C>T	p.Thr3350Ile	missense	Exon 55 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.10124C>T	p.Thr3375Ile	missense	Exon 55 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.10049C>T	p.Thr3350Ile	missense	Exon 55 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.10124C>T		non_coding_transcript_exon	Exon 55 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes AF: 0.00666 AC: 1013 AN: 152204 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00819

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00965

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00801 AC: 2015 AN: 251428 AF XY: 0.00882

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00708

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.00959

Gnomad OTH exome AF: 0.00978

GnomAD4 exome AF: 0.00875 AC: 12785 AN: 1461612 Hom.: 66 Cov.: 31 AF XY: 0.00902 AC XY: 6558 AN XY: 727118

African (AFR) AF: 0.00158 AC: 53 AN: 33478

American (AMR) AF: 0.00704 AC: 315 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 417 AN: 26130

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39684

South Asian (SAS) AF: 0.0113 AC: 975 AN: 86252

European-Finnish (FIN) AF: 0.00348 AC: 186 AN: 53416

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5768

European-Non Finnish (NFE) AF: 0.00922 AC: 10246 AN: 1111772

Other (OTH) AF: 0.00863 AC: 521 AN: 60388

GnomAD4 genome AF: 0.00663 AC: 1010 AN: 152322 Hom.: 6 Cov.: 32 AF XY: 0.00667 AC XY: 497 AN XY: 74484

African (AFR) AF: 0.00178 AC: 74 AN: 41568

American (AMR) AF: 0.00811 AC: 124 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00973 AC: 47 AN: 4828

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00966 AC: 657 AN: 68040

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.00865 Hom.: 17

Bravo AF: 0.00672

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0112 AC: 96

ExAC AF: 0.00810 AC: 984

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0114

EpiControl AF: 0.0122

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.43
DANN	Benign	0.85
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.099
Sift	Benign	0.21	T
Sift4G	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.17
MVP		0.60
MPC		0.13
ClinPred		0.0038	T
GERP RS		3.9
Varity_R		0.043
gMVP		0.24
Mutation Taster		=99/1	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: rs138127778; hg19: chr8-100861110;