Genetic Variant DSCAM:p.Arg1870Lys (chr21-40042448-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSCAM	NM_001389.5 link	c.5609G>A	p.Arg1870Lys	missense_variant	Exon 32 of 33	ENST00000400454.6	NP_001380.2	O60469-1
DSCAM	NM_001271534.3 link	c.5609G>A	p.Arg1870Lys	missense_variant	Exon 32 of 33		NP_001258463.1
DSCAM	XM_017028281.2 link	c.4901G>A	p.Arg1634Lys	missense_variant	Exon 29 of 30		XP_016883770.1
DSCAM	NR_073202.3 link	n.5915G>A		non_coding_transcript_exon_variant	Exon 32 of 33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DSCAM	ENST00000400454.6 link	c.5609G>A	p.Arg1870Lys	missense_variant	Exon 32 of 33	1	NM_001389.5	ENSP00000383303.1	O60469-1
DSCAM	ENST00000404019.2 link	c.4865G>A	p.Arg1622Lys	missense_variant	Exon 28 of 29	1		ENSP00000385342.2	Q8WY19
DSCAM	ENST00000617870.4 link	c.5114G>A	p.Arg1705Lys	missense_variant	Exon 29 of 30	5		ENSP00000478698.1	A0A087WUI7

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

Apr 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.

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