NM_017890.5:c.7227G>A

Variant names:

• chr8-99766875-G-A
• rs61753725
• NM_017890.5:c.7227G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_017890.5(VPS13B):​c.7227G>A​(p.Pro2409Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00504 in 1,613,950 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0051 (28 hom.)
• Consequence: VPS13B NM_017890.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.0180
• 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: 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 8-99766875-G-A is Benign according to our data. Variant chr8-99766875-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.018 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00413 (629/152234) while in subpopulation AMR AF = 0.00739 (113/15298). AF 95% confidence interval is 0.00628. There are 1 homozygotes in GnomAd4. There are 317 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	NM_017890.5	MANE Plus Clinical	c.7227G>A	p.Pro2409Pro	synonymous	Exon 40 of 62	NP_060360.3
	VPS13B	NM_152564.5	MANE Select	c.7152G>A	p.Pro2384Pro	synonymous	Exon 40 of 62	NP_689777.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13B	ENST00000358544.7	TSL:1 MANE Plus Clinical	c.7227G>A	p.Pro2409Pro	synonymous	Exon 40 of 62	ENSP00000351346.2
	VPS13B	ENST00000357162.7	TSL:1 MANE Select	c.7152G>A	p.Pro2384Pro	synonymous	Exon 40 of 62	ENSP00000349685.2
	VPS13B	ENST00000518569.1	TSL:3	n.282G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 626 AN: 152116 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000944

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00603

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00405 AC: 1016 AN: 251140 AF XY: 0.00414

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00486

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00569

Gnomad OTH exome AF: 0.00768

GnomAD4 exome AF: 0.00514 AC: 7510 AN: 1461716 Hom.: 28 Cov.: 31 AF XY: 0.00507 AC XY: 3685 AN XY: 727154

African (AFR) AF: 0.00128 AC: 43 AN: 33476

American (AMR) AF: 0.00521 AC: 233 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 281 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.000812 AC: 70 AN: 86254

European-Finnish (FIN) AF: 0.000805 AC: 43 AN: 53406

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5762

European-Non Finnish (NFE) AF: 0.00580 AC: 6444 AN: 1111932

Other (OTH) AF: 0.00591 AC: 357 AN: 60382

GnomAD4 genome AF: 0.00413 AC: 629 AN: 152234 Hom.: 1 Cov.: 31 AF XY: 0.00426 AC XY: 317 AN XY: 74430

African (AFR) AF: 0.00113 AC: 47 AN: 41544

American (AMR) AF: 0.00739 AC: 113 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.000944 AC: 10 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00603 AC: 410 AN: 68008

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

Alfa AF: 0.00489 Hom.: 2

Bravo AF: 0.00459

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00829

EpiControl AF: 0.00771

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Cohen syndrome (5)
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.5
DANN	Benign	0.62
PhyloP100		0.018
Mutation Taster		=98/2	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: rs61753725; hg19: chr8-100779103; COSMIC: COSV62137115;