21-40042669-T-G

Variant names:

• chr21-40042669-T-G
• rs181977833
• NM_001389.5:c.5388A>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001389.5(DSCAM):​c.5388A>C​(p.Arg1796Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000779 in 1,271,104 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00075 (4 hom.)
• Consequence: DSCAM NM_001389.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.122
• Publications: 0 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 21-40042669-T-G is Benign according to our data. Variant chr21-40042669-T-G is described in ClinVar as Benign. ClinVar VariationId is 742975.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.122 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00137 (77/56398) while in subpopulation SAS AF = 0.00563 (13/2310). AF 95% confidence interval is 0.00333. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 77 AD gene.

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.5388A>C	p.Arg1796Arg	synonymous	Exon 32 of 33	NP_001380.2
	DSCAM	NM_001271534.3		c.5388A>C	p.Arg1796Arg	synonymous	Exon 32 of 33	NP_001258463.1
	DSCAM	NR_073202.3		n.5694A>C		non_coding_transcript_exon	Exon 32 of 33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSCAM	ENST00000400454.6	TSL:1 MANE Select	c.5388A>C	p.Arg1796Arg	synonymous	Exon 32 of 33	ENSP00000383303.1	O60469-1
	DSCAM	ENST00000404019.2	TSL:1	c.4644A>C	p.Arg1548Arg	synonymous	Exon 28 of 29	ENSP00000385342.2	Q8WY19
	DSCAM	ENST00000617870.4	TSL:5	c.4893A>C	p.Arg1631Arg	synonymous	Exon 29 of 30	ENSP00000478698.1	A0A087WUI7

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 78 AN: 56274 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00447

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00605

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0294

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00153

GnomAD2 exomes AF: 0.00107 AC: 205 AN: 191766 AF XY: 0.00134

Gnomad AFR exome AF: 0.0000834

Gnomad AMR exome AF: 0.000677

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000641

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.000752 AC: 913 AN: 1214706 Hom.: 4 Cov.: 31 AF XY: 0.000943 AC XY: 553 AN XY: 586716

African (AFR) AF: 0.000407 AC: 11 AN: 27028

American (AMR) AF: 0.000810 AC: 23 AN: 28398

Ashkenazi Jewish (ASJ) AF: 0.0000968 AC: 2 AN: 20652

East Asian (EAS) AF: 0.00 AC: 0 AN: 30642

South Asian (SAS) AF: 0.00885 AC: 328 AN: 37052

European-Finnish (FIN) AF: 0.0000505 AC: 2 AN: 39612

Middle Eastern (MID) AF: 0.00557 AC: 27 AN: 4848

European-Non Finnish (NFE) AF: 0.000470 AC: 459 AN: 977536

Other (OTH) AF: 0.00125 AC: 61 AN: 48938

GnomAD4 genome AF: 0.00137 AC: 77 AN: 56398 Hom.: 0 Cov.: 0 AF XY: 0.00145 AC XY: 40 AN XY: 27624

African (AFR) AF: 0.000446 AC: 6 AN: 13438

American (AMR) AF: 0.00446 AC: 21 AN: 4710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1308

East Asian (EAS) AF: 0.00 AC: 0 AN: 2434

South Asian (SAS) AF: 0.00563 AC: 13 AN: 2310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5494

Middle Eastern (MID) AF: 0.0326 AC: 3 AN: 92

European-Non Finnish (NFE) AF: 0.00129 AC: 33 AN: 25596

Other (OTH) AF: 0.00149 AC: 1 AN: 670

Alfa AF: 0.00145 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.2
DANN	Benign	0.69
PhyloP100		-0.12
Mutation Taster		=95/5	polymorphism

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: rs181977833; hg19: chr21-41414596;