chr21-40042468-AG-A

Position:

• chr21-40042468-AG-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001389.5(DSCAM):​c.5588del​(p.Pro1863LeufsTer22) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSCAM NM_001389.5 frameshift
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.88

Genes affected

DSCAM (HGNC:3039): (DS cell adhesion molecule) This gene is a member of the immunoglobulin superfamily of cell adhesion molecules (Ig-CAMs), and is involved in human central and peripheral nervous system development. This gene is a candidate for Down syndrome and congenital heart disease (DSCHD). A gene encoding a similar Ig-CAM protein is located on chromosome 11. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0747 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSCAM	NM_001389.5	c.5588del	p.Pro1863LeufsTer22	frameshift_variant	32/33	ENST00000400454.6	NP_001380.2
DSCAM	NM_001271534.3	c.5588del	p.Pro1863LeufsTer22	frameshift_variant	32/33		NP_001258463.1
DSCAM	XM_017028281.2	c.4880del	p.Pro1627LeufsTer22	frameshift_variant	29/30		XP_016883770.1
DSCAM	NR_073202.3	n.5894del		non_coding_transcript_exon_variant	32/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSCAM	ENST00000400454.6	c.5588del	p.Pro1863LeufsTer22	frameshift_variant	32/33	1	NM_001389.5	ENSP00000383303	P1
DSCAM	ENST00000404019.2	c.4844del	p.Pro1615LeufsTer22	frameshift_variant	28/29	1		ENSP00000385342
DSCAM	ENST00000617870.4	c.5093del	p.Pro1698LeufsTer22	frameshift_variant	29/30	5		ENSP00000478698

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Jun 12, 2017

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Computational scores

Source: dbNSFP v4.3

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: rs1555869463; hg19: chr21-41414395;