21-40461957-T-C

Variant names:

• chr21-40461957-T-C
• rs2222973
• NM_001389.5:c.509-92712A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001389.5(DSCAM):​c.509-92712A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 152,082 control chromosomes in the GnomAD database, including 10,878 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 0.36 (10878 hom., cov: 32)
• Consequence: DSCAM NM_001389.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.55
• Publications: 13 publications found

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]

DSCAM Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001389.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSCAM	NM_001389.5	MANE Select	c.509-92712A>G		intron	N/A	NP_001380.2
	DSCAM	NM_001271534.3		c.509-92712A>G		intron	N/A	NP_001258463.1
	DSCAM	NR_073202.3		n.1006-92712A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSCAM	ENST00000400454.6	TSL:1 MANE Select	c.509-92712A>G		intron	N/A	ENSP00000383303.1	O60469-1

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54114 AN: 151964 Hom.: 10841 Cov.: 32

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.356

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.333

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.356 AC: 54195 AN: 152082 Hom.: 10878 Cov.: 32 AF XY: 0.358 AC XY: 26576 AN XY: 74318

African (AFR) AF: 0.535 AC: 22187 AN: 41490

American (AMR) AF: 0.373 AC: 5695 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 1236 AN: 3470

East Asian (EAS) AF: 0.294 AC: 1520 AN: 5162

South Asian (SAS) AF: 0.427 AC: 2051 AN: 4808

European-Finnish (FIN) AF: 0.268 AC: 2832 AN: 10566

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17654 AN: 67994

Other (OTH) AF: 0.332 AC: 699 AN: 2108

Alfa AF: 0.295 Hom.: 27542

Bravo AF: 0.372

Asia WGS AF: 0.384 AC: 1335 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.031
DANN	Benign	0.42
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2222973; hg19: chr21-41833884;