Variant chr21-37228256-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006052.2(VPS26C):c.625G>A(p.Val209Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,612,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

VPS26C
NM_006052.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.43

Variant links:

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]

VPS26C links:

VPS26C (HGNC:):

VPS26C links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19573876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS26C	NM_006052.2 linkuse as main transcript	c.625G>A	p.Val209Met	missense_variant	6/8	ENST00000309117.11	NP_006043.1	O14972-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS26C	ENST00000309117.11 linkuse as main transcript	c.625G>A	p.Val209Met	missense_variant	6/8	1	NM_006052.2	ENSP00000311399.6		O14972-1

Frequencies

GnomAD3 genomes

AF:

0.0000528

AC:

AN:

151372

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.0000737

Gnomad OTH

AF:

0.000483

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

250998

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000114

AC:

167

AN:

1460788

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

726680

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000124

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000528

AC:

AN:

151490

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74050

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000737

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.0000453

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The c.625G>A (p.V209M) alteration is located in exon 6 (coding exon 6) of the DSCR3 gene. This alteration results from a G to A substitution at nucleotide position 625, causing the valine (V) at amino acid position 209 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.38

LIST_S2

Uncertain

0.86

D;T;T;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

0.92

N;N;N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.2

N;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

0.97

.;D;.;.

Vest4

0.39

MutPred

0.58

Loss of sheet (P = 0.0457);.;.;.;

MVP

0.20

MPC

0.82

ClinPred

0.26

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over