rs145279584

chr8-99853629-T-Cchr8-99853629-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_017890.5(VPS13B):c.10315T>C(p.Leu3439=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,614,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: VPS13B NM_017890.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0890

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 8-99853629-T-C is Benign according to our data. Variant chr8-99853629-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197995.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
• BP7: Synonymous conserved (PhyloP=-0.089 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.10315T>C	p.Leu3439=	synonymous_variant	56/62	ENST00000358544.7
VPS13B	NM_152564.5	c.10240T>C	p.Leu3414=	synonymous_variant	56/62	ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000358544.7	c.10315T>C	p.Leu3439=	synonymous_variant	56/62	1	NM_017890.5
VPS13B	ENST00000357162.7	c.10240T>C	p.Leu3414=	synonymous_variant	56/62	1	NM_152564.5	P1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251478 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135914

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000896 AC: 131 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.0000921 AC XY: 67 AN XY: 727244

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74480

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000421 Hom.: 0

Bravo AF: 0.000892

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cohen syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 01, 2015

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 05, 2016

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.23
Dann	Benign	0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs145279584; hg19: chr8-100865857;