21-37227731-C-T

Position:

• chr21-37227731-C-T

Variant summary

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

The NM_006052.2(VPS26C):​c.734G>A​(p.Gly245Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: VPS26C NM_006052.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.11

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 (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/exons	MANE	Protein	UniProt
VPS26C	NM_006052.2	c.734G>A	p.Gly245Asp	missense_variant	7/8	ENST00000309117.11	NP_006043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS26C	ENST00000309117.11	c.734G>A	p.Gly245Asp	missense_variant	7/8	1	NM_006052.2	ENSP00000311399.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2024

The c.734G>A (p.G245D) alteration is located in exon 7 (coding exon 7) of the DSCR3 gene. This alteration results from a G to A substitution at nucleotide position 734, causing the glycine (G) at amino acid position 245 to be replaced by an aspartic acid (D). 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	0.13
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	0.0048
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.0088	T
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.80	T
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Benign	0.13
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.050	.;B;.;.
Vest4		0.55
MutPred		0.66		Gain of solvent accessibility (P = 0.039);.;.;.;
MVP		0.29
MPC		0.69
ClinPred		0.89	D
GERP RS		4.2
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-38600032;