rs9305614

Positions:

• chr21-37237438-A-G
• chr21-37237438-A-T
• chr21-37237438-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006052.2(VPS26C):​c.351+1022T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 152,050 control chromosomes in the GnomAD database, including 13,719 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (13717 hom., cov: 32)
  • Exomes 𝑓: 0.70 (2 hom.)
• Consequence: VPS26C NM_006052.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.140

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS26C	NM_006052.2	c.351+1022T>C		intron_variant		ENST00000309117.11	NP_006043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS26C	ENST00000309117.11	c.351+1022T>C		intron_variant		1	NM_006052.2	ENSP00000311399	P1
	ENST00000440629.1	n.214A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63778 AN: 151920 Hom.: 13700 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.374

Gnomad ASJ AF: 0.378

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.433

GnomAD4 exome AF: 0.700 AC: 7 AN: 10 Hom.: 2 Cov.: 0 AF XY: 0.833 AC XY: 5 AN XY: 6

Gnomad4 FIN exome AF: 0.750

Gnomad4 NFE exome AF: 0.667

GnomAD4 genome AF: 0.420 AC: 63835 AN: 152040 Hom.: 13717 Cov.: 32 AF XY: 0.423 AC XY: 31416 AN XY: 74332

Gnomad4 AFR AF: 0.376

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.378

Gnomad4 EAS AF: 0.512

Gnomad4 SAS AF: 0.500

Gnomad4 FIN AF: 0.498

Gnomad4 NFE AF: 0.435

Gnomad4 OTH AF: 0.440

Alfa AF: 0.424 Hom.: 18655

Bravo AF: 0.406

Asia WGS AF: 0.527 AC: 1833 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.9
DANN	Benign	0.52

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: rs9305614; hg19: chr21-38609739;