rs114120664

Variant names:

• chr8-99192993-T-C
• rs114120664
• NM_017890.5:c.2451T>C

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.2451T>C​(p.His817His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,613,750 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (8 hom.)
• Consequence: VPS13B NM_152564.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.833
• Publications: 1 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 (BayesDel_noAF=-0.54).
• BP6: Variant 8-99192993-T-C is Benign according to our data. Variant chr8-99192993-T-C is described in ClinVar as Benign. ClinVar VariationId is 262659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0059 (898/152268) while in subpopulation AFR AF = 0.0176 (731/41564). AF 95% confidence interval is 0.0165. There are 7 homozygotes in GnomAd4. There are 421 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.2451T>C	p.His817His	synonymous	Exon 17 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.2451T>C	p.His817His	synonymous	Exon 17 of 62	NP_689777.3
	VPS13B	NM_015243.3		c.2451T>C	p.His817His	synonymous	Exon 17 of 18	NP_056058.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.2451T>C	p.His817His	synonymous	Exon 17 of 62	ENSP00000351346.2	Q7Z7G8-1
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.2451T>C	p.His817His	synonymous	Exon 17 of 62	ENSP00000349685.2	Q7Z7G8-2
	VPS13B	ENST00000355155.6	TSL:1	n.2451T>C		non_coding_transcript_exon	Exon 17 of 28	ENSP00000347281.2	A0A8C8KE22

Frequencies

GnomAD3 genomes AF: 0.00589 AC: 896 AN: 152150 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00272 AC: 683 AN: 251226 AF XY: 0.00241

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00133 AC: 1943 AN: 1461482 Hom.: 8 Cov.: 31 AF XY: 0.00125 AC XY: 911 AN XY: 727048

African (AFR) AF: 0.0188 AC: 629 AN: 33464

American (AMR) AF: 0.00304 AC: 136 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 390 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86250

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53336

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5762

European-Non Finnish (NFE) AF: 0.000476 AC: 529 AN: 1111836

Other (OTH) AF: 0.00335 AC: 202 AN: 60376

GnomAD4 genome AF: 0.00590 AC: 898 AN: 152268 Hom.: 7 Cov.: 32 AF XY: 0.00565 AC XY: 421 AN XY: 74462

African (AFR) AF: 0.0176 AC: 731 AN: 41564

American (AMR) AF: 0.00385 AC: 59 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000574 AC: 39 AN: 67994

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00413 Hom.: 2

Bravo AF: 0.00674

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00147

EpiControl AF: 0.00154

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Cohen syndrome (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.8
DANN	Benign	0.35
PhyloP100		0.83
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: rs114120664; hg19: chr8-100205221;