21-37232386-G-T

Variant names:

• chr21-37232386-G-T
• rs757477154
• NM_006052.2:c.498C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006052.2(VPS26C):​c.498C>A​(p.Asn166Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS26C NM_006052.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.175

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]

ENSG00000242553 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS26C	NM_006052.2	c.498C>A	p.Asn166Lys	missense_variant	Exon 5 of 8	ENST00000309117.11	NP_006043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS26C	ENST00000309117.11	c.498C>A	p.Asn166Lys	missense_variant	Exon 5 of 8	1	NM_006052.2	ENSP00000311399.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.498C>A (p.N166K) alteration is located in exon 5 (coding exon 5) of the DSCR3 gene. This alteration results from a C to A substitution at nucleotide position 498, causing the asparagine (N) at amino acid position 166 to be replaced by a lysine (K). 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	Pathogenic	0.69
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.17
DANN	Benign	0.91
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	0.29	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.99	.;D;.;.
Vest4		0.90
MutPred		0.56		Gain of sheet (P = 0.0125);.;.;.;
MVP		0.50
MPC		1.0
ClinPred		0.94	D
GERP RS		-10
gMVP		0.67

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: rs757477154; hg19: chr21-38604687;