Variant chr21-40042448-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001389.5(DSCAM):c.5609G>A(p.Arg1870Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

DSCAM
NM_001389.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.81

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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
DSCAM	NM_001389.5 linkuse as main transcript	c.5609G>A	p.Arg1870Lys	missense_variant	32/33	ENST00000400454.6	NP_001380.2
DSCAM	NM_001271534.3 linkuse as main transcript	c.5609G>A	p.Arg1870Lys	missense_variant	32/33		NP_001258463.1
DSCAM	XM_017028281.2 linkuse as main transcript	c.4901G>A	p.Arg1634Lys	missense_variant	29/30		XP_016883770.1
DSCAM	NR_073202.3 linkuse as main transcript	n.5915G>A		non_coding_transcript_exon_variant	32/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSCAM	ENST00000400454.6 linkuse as main transcript	c.5609G>A	p.Arg1870Lys	missense_variant	32/33	1	NM_001389.5	ENSP00000383303	P1	O60469-1
DSCAM	ENST00000404019.2 linkuse as main transcript	c.4865G>A	p.Arg1622Lys	missense_variant	28/29	1		ENSP00000385342
DSCAM	ENST00000617870.4 linkuse as main transcript	c.5114G>A	p.Arg1705Lys	missense_variant	29/30	5		ENSP00000478698

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.5609G>A (p.R1870K) alteration is located in exon 32 (coding exon 32) of the DSCAM gene. This alteration results from a G to A substitution at nucleotide position 5609, causing the arginine (R) at amino acid position 1870 to be replaced by a lysine (K). 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

Benign

0.24

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;.

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.90

L;.;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.5

N;.;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.013

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.98

D;.;.

Vest4

0.90

MutPred

0.30

Gain of ubiquitination at R1870 (P = 0.0051);.;.;

MVP

0.88

MPC

1.5

ClinPred

0.98

GERP RS

5.3

Varity_R

0.45

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over