chr21-37240615-T-C

Variant names:

• chr21-37240615-T-C
• rs143567273
• NM_006052.2:c.82A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006052.2(VPS26C):​c.82A>G​(p.Ile28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000276 in 1,614,134 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: VPS26C NM_006052.2 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.00400

Genes affected

VPS26C (HGNC:3044): (VPS26 endosomal protein sorting factor C) The region of chromosome 21 between genes CBR and ERG (CBR-ERG region), which spans 2.5 Mb on 21q22.2, has been defined by analysis of patients with partial trisomy 21. It contributes significantly to the pathogenesis of many characteristics of Down syndrome, including morphological features, hypotonia, and cognitive disability. The DSCR3 (Down syndrome critical region gene 3) gene is found in this region and is predictated to contain eight exons. DSCR3 is expressed in most tissues examined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00559026).
• BP6: Variant 21-37240615-T-C is Benign according to our data. Variant chr21-37240615-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3034062.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS26C	NM_006052.2	c.82A>G	p.Ile28Val	missense_variant	Exon 2 of 8	ENST00000309117.11	NP_006043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS26C	ENST00000309117.11	c.82A>G	p.Ile28Val	missense_variant	Exon 2 of 8	1	NM_006052.2	ENSP00000311399.6

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 197 AN: 152204 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000330 AC: 83 AN: 251214 AF XY: 0.000236

Gnomad AFR exome AF: 0.00431

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000170 AC: 249 AN: 1461812 Hom.: 1 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 727212

Gnomad4 AFR exome AF: 0.00478 AC: 160 AN: 33474

Gnomad4 AMR exome AF: 0.000291 AC: 13 AN: 44716

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26130

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.0000348 AC: 3 AN: 86250

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53412

Gnomad4 NFE exome AF: 0.0000459 AC: 51 AN: 1111966

Gnomad4 Remaining exome AF: 0.000331 AC: 20 AN: 60396

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152322 Hom.: 1 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74478

Gnomad4 AFR AF: 0.00423 AC: 0.00423321 AN: 0.00423321

Gnomad4 AMR AF: 0.000327 AC: 0.000326968 AN: 0.000326968

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207297 AN: 0.000207297

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000176 AC: 0.000176382 AN: 0.000176382

Gnomad4 OTH AF: 0.00142 AC: 0.00141777 AN: 0.00141777

Alfa AF: 0.000590 Hom.: 0

Bravo AF: 0.00128

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000469 AC: 57

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

VPS26C-related disorder Benign:1

Apr 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.6
DANN	Benign	0.74
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.074
Sift	Benign	0.71	T;T
Sift4G	Benign	0.57	T;T
Vest4		0.15
MVP		0.27
MPC		0.41
ClinPred		0.0074	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.082
Mutation Taster		=97/3	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

Publications

LitVar

Other links and lift over

dbSNP: rs143567273; hg19: chr21-38612916;