21-40042597-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001389.5(DSCAM):c.5460C>T(p.His1820=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,614,102 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (2 hom.)
• Consequence: DSCAM NM_001389.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.195

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 21-40042597-G-A is Benign according to our data. Variant chr21-40042597-G-A is described in ClinVar as [Benign]. Clinvar id is 726823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.195 with no splicing effect.
• BS2: High AC in GnomAd at 514 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSCAM	NM_001389.5	c.5460C>T	p.His1820=	synonymous_variant	32/33	ENST00000400454.6
DSCAM	NM_001271534.3	c.5460C>T	p.His1820=	synonymous_variant	32/33
DSCAM	XM_017028281.2	c.4752C>T	p.His1584=	synonymous_variant	29/30
DSCAM	NR_073202.3	n.5766C>T		non_coding_transcript_exon_variant	32/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSCAM	ENST00000400454.6	c.5460C>T	p.His1820=	synonymous_variant	32/33	1	NM_001389.5	P1
DSCAM	ENST00000404019.2	c.4716C>T	p.His1572=	synonymous_variant	28/29	1
DSCAM	ENST00000617870.4	c.4965C>T	p.His1655=	synonymous_variant	29/30	5

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152126 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00101 AC: 252 AN: 249560 Hom.: 2 AF XY: 0.000746 AC XY: 101 AN XY: 135392

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000475 AC: 694 AN: 1461856 Hom.: 2 Cov.: 31 AF XY: 0.000406 AC XY: 295 AN XY: 727236

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00154

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152246 Hom.: 5 Cov.: 33 AF XY: 0.00329 AC XY: 245 AN XY: 74432

Gnomad4 AFR AF: 0.0115

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00186 Hom.: 1

Bravo AF: 0.00391

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2018

- -

DSCAM-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 27, 2023

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	1.4
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: rs114741050; hg19: chr21-41414524; COSMIC: COSV68022363;