21-40044115-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Moderate BP6_Moderate BS2

The NM_001389.5(DSCAM):c.5346G>C(p.Glu1782Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: DSCAM NM_001389.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.98

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 -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DSCAM
• BP4: Computational evidence support a benign effect (MetaRNN=0.25736585).
• BP6: Variant 21-40044115-C-G is Benign according to our data. Variant chr21-40044115-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2346659.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSCAM	NM_001389.5	c.5346G>C	p.Glu1782Asp	missense_variant	31/33	ENST00000400454.6
DSCAM	NM_001271534.3	c.5346G>C	p.Glu1782Asp	missense_variant	31/33
DSCAM	XM_017028281.2	c.4638G>C	p.Glu1546Asp	missense_variant	28/30
DSCAM	NR_073202.3	n.5652G>C		non_coding_transcript_exon_variant	31/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSCAM	ENST00000400454.6	c.5346G>C	p.Glu1782Asp	missense_variant	31/33	1	NM_001389.5	P1
DSCAM	ENST00000404019.2	c.4602G>C	p.Glu1534Asp	missense_variant	27/29	1
DSCAM	ENST00000617870.4	c.4851G>C	p.Glu1617Asp	missense_variant	28/30	5

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000881 AC: 22 AN: 249634 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135404

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.0000866 AC XY: 63 AN XY: 727176

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.0000907 AC: 11

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	0.66	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N;.;N
REVEL	Benign	0.23
Sift	Uncertain	0.029	D;.;D
Sift4G	Benign	0.068	T;T;T
Polyphen		0.99	D;.;.
Vest4		0.50
MutPred		0.27		Loss of sheet (P = 0.0228);.;.;
MVP		0.70
MPC		1.4
ClinPred		0.28	T
GERP RS		2.3
Varity_R		0.21
gMVP		0.42

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: rs373304031; hg19: chr21-41416042;