8-99875122-T-C

Position:

• chr8-99875122-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017890.5(VPS13B):​c.11821-296T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 419,322 control chromosomes in the GnomAD database, including 3,730 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1297 hom., cov: 32)
  • Exomes 𝑓: 0.13 (2433 hom.)
• Consequence: VPS13B NM_017890.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.854

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]

COX6C (HGNC:2285): (cytochrome c oxidase subunit 6C) Cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes subunit VIc, which has 77% amino acid sequence identity with mouse subunit VIc. This gene is up-regulated in prostate cancer cells. A pseudogene has been found on chromosomes 16p12. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-99875122-T-C is Benign according to our data. Variant chr8-99875122-T-C is described in ClinVar as [Benign]. Clinvar id is 1266835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13B	NM_017890.5	c.11821-296T>C		intron_variant		ENST00000358544.7
VPS13B	NM_152564.5	c.11746-296T>C		intron_variant		ENST00000357162.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13B	ENST00000357162.7	c.11746-296T>C		intron_variant		1	NM_152564.5	P1
VPS13B	ENST00000358544.7	c.11821-296T>C		intron_variant		1	NM_017890.5

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19475 AN: 152098 Hom.: 1299 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.0932

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.128 AC: 34217 AN: 267106 Hom.: 2433 Cov.: 2 AF XY: 0.127 AC XY: 18102 AN XY: 142578

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.137

Gnomad4 ASJ exome AF: 0.203

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.128 AC: 19478 AN: 152216 Hom.: 1297 Cov.: 32 AF XY: 0.126 AC XY: 9396 AN XY: 74416

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.204

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.0935

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.124

Alfa AF: 0.134 Hom.: 502

Bravo AF: 0.132

Asia WGS AF: 0.116 AC: 404 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.37
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs10955222; hg19: chr8-100887350;