Variant chr21-40013231-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001389.5(DSCAM):c.5842A>G(p.Met1948Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DSCAM
NM_001389.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88

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 Likely_benign. Variant got -5 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.09561834).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSCAM	NM_001389.5 linkuse as main transcript	c.5842A>G	p.Met1948Val	missense_variant	33/33	ENST00000400454.6	NP_001380.2
DSCAM	NM_001271534.3 linkuse as main transcript	c.5788A>G	p.Met1930Val	missense_variant	33/33		NP_001258463.1
DSCAM	XM_017028281.2 linkuse as main transcript	c.5134A>G	p.Met1712Val	missense_variant	30/30		XP_016883770.1
DSCAM	NR_073202.3 linkuse as main transcript	n.6148A>G		non_coding_transcript_exon_variant	33/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSCAM	ENST00000400454.6 linkuse as main transcript	c.5842A>G	p.Met1948Val	missense_variant	33/33	1	NM_001389.5	ENSP00000383303	P1	O60469-1
DSCAM	ENST00000404019.2 linkuse as main transcript	c.5044A>G	p.Met1682Val	missense_variant	29/29	1		ENSP00000385342
DSCAM	ENST00000617870.4 linkuse as main transcript	c.5347A>G	p.Met1783Val	missense_variant	30/30	5		ENSP00000478698

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248698

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134940

show subpopulations

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

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

Jan 30, 2024

The c.5842A>G (p.M1948V) alteration is located in exon 33 (coding exon 33) of the DSCAM gene. This alteration results from a A to G substitution at nucleotide position 5842, causing the methionine (M) at amino acid position 1948 to be replaced by a valine (V). 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

0.063

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.053

T;.;.

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.096

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.;.

MutationTaster

Benign

0.97

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.28

N;.;N

REVEL

Benign

0.14

Sift

Benign

0.53

T;.;T

Sift4G

Benign

0.35

T;T;T

Polyphen

0.0020

B;.;.

Vest4

0.33

MVP

0.48

MPC

0.54

ClinPred

0.084

GERP RS

2.8

Varity_R

0.17

gMVP

0.19

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