NM_017890.5:c.3837C>T

Variant names:

• chr8-99481769-C-T
• rs34941871
• NM_017890.5:c.3837C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_017890.5(VPS13B):​c.3837C>T​(p.Cys1279Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,613,912 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (106 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (86 hom.)
• Consequence: VPS13B NM_017890.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.01
• Publications: 2 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: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 8-99481769-C-T is Benign according to our data. Variant chr8-99481769-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0651 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017890.5. 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.3837C>T	p.Cys1279Cys	synonymous	Exon 25 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.3837C>T	p.Cys1279Cys	synonymous	Exon 25 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.3837C>T	p.Cys1279Cys	synonymous	Exon 25 of 62	ENSP00000351346.2
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.3837C>T	p.Cys1279Cys	synonymous	Exon 25 of 62	ENSP00000349685.2
	VPS13B	ENST00000355155.6	TSL:1	n.3834C>T		non_coding_transcript_exon	Exon 25 of 28	ENSP00000347281.2

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2932 AN: 152146 Hom.: 107 Cov.: 32

Gnomad AFR AF: 0.0672

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00517 AC: 1297 AN: 251038 AF XY: 0.00383

Gnomad AFR exome AF: 0.0693

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000970

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00193 AC: 2815 AN: 1461648 Hom.: 86 Cov.: 31 AF XY: 0.00173 AC XY: 1259 AN XY: 727130

African (AFR) AF: 0.0690 AC: 2308 AN: 33472

American (AMR) AF: 0.00347 AC: 155 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5766

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111818

Other (OTH) AF: 0.00376 AC: 227 AN: 60386

GnomAD4 genome AF: 0.0193 AC: 2938 AN: 152264 Hom.: 106 Cov.: 32 AF XY: 0.0185 AC XY: 1376 AN XY: 74450

African (AFR) AF: 0.0672 AC: 2790 AN: 41536

American (AMR) AF: 0.00647 AC: 99 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

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

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68022

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.00850 Hom.: 22

Bravo AF: 0.0222

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.7
DANN	Benign	0.64
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs34941871; hg19: chr8-100493997;