21-40013093-C-G

Variant names:

• chr21-40013093-C-G
• rs370041442
• NM_001389.5:c.5980G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001389.5(DSCAM):​c.5980G>C​(p.Asp1994His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1994N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSCAM NM_001389.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.34
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.5980G>C	p.Asp1994His	missense	Exon 33 of 33	NP_001380.2
	DSCAM	NM_001271534.3		c.5926G>C	p.Asp1976His	missense	Exon 33 of 33	NP_001258463.1
	DSCAM	NR_073202.3		n.6286G>C		non_coding_transcript_exon	Exon 33 of 33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSCAM	ENST00000400454.6	TSL:1 MANE Select	c.5980G>C	p.Asp1994His	missense	Exon 33 of 33	ENSP00000383303.1	O60469-1
	DSCAM	ENST00000404019.2	TSL:1	c.5182G>C	p.Asp1728His	missense	Exon 29 of 29	ENSP00000385342.2	Q8WY19
	DSCAM	ENST00000617870.4	TSL:5	c.5485G>C	p.Asp1829His	missense	Exon 30 of 30	ENSP00000478698.1	A0A087WUI7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	-0.018	T
MutationAssessor	Benign	1.9	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.14		Gain of MoRF binding (P = 0.0376)
MVP		0.77
MPC		0.64
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.50
gMVP		0.40
Mutation Taster		=13/87	disease causing

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: rs370041442; hg19: chr21-41385020;