11-117428405-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_020693.4(DSCAML1):​c.6085G>A​(p.Glu2029Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000299 in 1,570,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

DSCAML1
NM_020693.4 missense

Scores

5
8
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.42
Variant links:
Genes affected
DSCAML1 (HGNC:14656): (DS cell adhesion molecule like 1) The protein encoded by this gene is a member of the Ig superfamily of cell adhesion molecules and is involved in neuronal differentiation. The encoded membrane-bound protein localizes to the cell surface, where it forms aggregates that repel neuronal processes of the same cell type. [provided by RefSeq, Sep 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DSCAML1. . Gene score misZ 3.15 (greater than the threshold 3.09). Trascript score misZ 4.5764 (greater than threshold 3.09). GenCC has associacion of gene with motor neuron disorder, retinal disorder.
BS2
High AC in GnomAdExome4 at 45 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DSCAML1NM_020693.4 linkuse as main transcriptc.6085G>A p.Glu2029Lys missense_variant 33/33 ENST00000651296.2 NP_065744.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DSCAML1ENST00000651296.2 linkuse as main transcriptc.6085G>A p.Glu2029Lys missense_variant 33/33 NM_020693.4 ENSP00000498769 Q8TD84-1
DSCAML1ENST00000321322.6 linkuse as main transcriptc.6265G>A p.Glu2089Lys missense_variant 33/331 ENSP00000315465 P1
DSCAML1ENST00000651172.1 linkuse as main transcriptc.6265G>A p.Glu2089Lys missense_variant 33/33 ENSP00000498407 P1
DSCAML1ENST00000527706.5 linkuse as main transcriptc.5455G>A p.Glu1819Lys missense_variant 31/315 ENSP00000434335 Q8TD84-2

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152080
Hom.:
0
Cov.:
31
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000331
AC:
7
AN:
211592
Hom.:
0
AF XY:
0.0000343
AC XY:
4
AN XY:
116458
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000128
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000487
Gnomad NFE exome
AF:
0.0000396
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000317
AC:
45
AN:
1418848
Hom.:
0
Cov.:
33
AF XY:
0.0000369
AC XY:
26
AN XY:
704058
show subpopulations
Gnomad4 AFR exome
AF:
0.0000650
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000509
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000356
Gnomad4 OTH exome
AF:
0.0000171
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152080
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74292
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000509
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 25, 2023The c.6265G>A (p.E2089K) alteration is located in exon 33 (coding exon 33) of the DSCAML1 gene. This alteration results from a G to A substitution at nucleotide position 6265, causing the glutamic acid (E) at amino acid position 2089 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 21, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 2177011). This variant has not been reported in the literature in individuals affected with DSCAML1-related conditions. This variant is present in population databases (rs762186342, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2089 of the DSCAML1 protein (p.Glu2089Lys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
26
DANN
Uncertain
1.0
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.069
D
MetaRNN
Uncertain
0.74
D;D
MetaSVM
Benign
-0.67
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Benign
-1.4
N;N
REVEL
Uncertain
0.42
Sift
Uncertain
0.010
D;D
Sift4G
Uncertain
0.023
D;D
Vest4
0.89
MVP
0.88
MPC
0.0090
ClinPred
0.34
T
GERP RS
4.8
gMVP
0.44

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.

Other links and lift over

dbSNP: rs762186342; hg19: chr11-117299121; COSMIC: COSV99074331; API