chr8-99642091-C-T

Variant names:

• chr8-99642091-C-T
• rs144257406
• NM_017890.5:c.5576C>T

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.5501C>T​(p.Ser1834Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,614,046 control chromosomes in the GnomAD database, including 97 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. S1834S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (92 hom.)
• Consequence: VPS13B NM_152564.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.212
• Publications: 9 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=0.0017789304).
• BP6: Variant 8-99642091-C-T is Benign according to our data. Variant chr8-99642091-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0521 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.5576C>T	p.Ser1859Leu	missense	Exon 34 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.5501C>T	p.Ser1834Leu	missense	Exon 34 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.5576C>T	p.Ser1859Leu	missense	Exon 34 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.5501C>T	p.Ser1834Leu	missense	Exon 34 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000682153.1		n.5576C>T		non_coding_transcript_exon	Exon 34 of 62	ENSP00000507923.1	A0A804HKG9

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152134 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00869 AC: 2178 AN: 250702 AF XY: 0.00622

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.0611

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00572

GnomAD4 exome AF: 0.00176 AC: 2580 AN: 1461794 Hom.: 92 Cov.: 31 AF XY: 0.00144 AC XY: 1046 AN XY: 727188

African (AFR) AF: 0.000358 AC: 12 AN: 33478

American (AMR) AF: 0.0539 AC: 2408 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.000453 AC: 18 AN: 39696

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111990

Other (OTH) AF: 0.00132 AC: 80 AN: 60392

GnomAD4 genome AF: 0.00219 AC: 333 AN: 152252 Hom.: 5 Cov.: 32 AF XY: 0.00224 AC XY: 167 AN XY: 74434

African (AFR) AF: 0.00111 AC: 46 AN: 41556

American (AMR) AF: 0.0173 AC: 265 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.000712 Hom.: 3

Bravo AF: 0.00494

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00707 AC: 858

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.77
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.21
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.078
Sift	Benign	0.50	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.25
MVP		0.37
MPC		0.11
ClinPred		0.0031	T
GERP RS		0.15
Varity_R		0.028
gMVP		0.22
Mutation Taster		=92/8	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: rs144257406; hg19: chr8-100654319; COSMIC: COSV62148597; COSMIC: COSV62148597;