chr21-40042427-T-A

Position:

• chr21-40042427-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000400454.6(DSCAM):​c.5630A>T​(p.Lys1877Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DSCAM ENST00000400454.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DSCAM. . Gene score misZ 3.2228 (greater than the threshold 3.09). Trascript score misZ 4.4297 (greater than threshold 3.09). GenCC has associacion of gene with autism spectrum disorder.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSCAM	NM_001389.5	c.5630A>T	p.Lys1877Ile	missense_variant	32/33	ENST00000400454.6	NP_001380.2
DSCAM	NM_001271534.3	c.5630A>T	p.Lys1877Ile	missense_variant	32/33		NP_001258463.1
DSCAM	XM_017028281.2	c.4922A>T	p.Lys1641Ile	missense_variant	29/30		XP_016883770.1
DSCAM	NR_073202.3	n.5936A>T		non_coding_transcript_exon_variant	32/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSCAM	ENST00000400454.6	c.5630A>T	p.Lys1877Ile	missense_variant	32/33	1	NM_001389.5	ENSP00000383303	P1
DSCAM	ENST00000404019.2	c.4886A>T	p.Lys1629Ile	missense_variant	28/29	1		ENSP00000385342
DSCAM	ENST00000617870.4	c.5135A>T	p.Lys1712Ile	missense_variant	29/30	5		ENSP00000478698

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.5630A>T (p.K1877I) alteration is located in exon 32 (coding exon 32) of the DSCAM gene. This alteration results from a A to T substitution at nucleotide position 5630, causing the lysine (K) at amino acid position 1877 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.3	D;.;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.77
MutPred		0.35		Loss of catalytic residue at K1877 (P = 9e-04);.;.;
MVP		0.84
MPC		2.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.51
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-41414354;