chr11-83471718-G-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001142699.3(DLG2):​c.2354C>T​(p.Thr785Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

DLG2
NM_001142699.3 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.04

Publications

4 publications found
Variant links:
Genes affected
DLG2 (HGNC:2901): (discs large MAGUK scaffold protein 2) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. The encoded protein forms a heterodimer with a related family member that may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Multiple transcript variants encoding different isoforms have been found for this gene. Additional transcript variants have been described, but their full-length nature is not known. [provided by RefSeq, Dec 2008]
DLG2 Gene-Disease associations (from GenCC):
  • delayed puberty, self-limited
    Inheritance: AD, AR Classification: LIMITED Submitted by: Ambry Genetics
  • neurodevelopmental disorder
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.30602828).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DLG2NM_001142699.3 linkc.2354C>T p.Thr785Ile missense_variant Exon 24 of 28 ENST00000376104.7 NP_001136171.1 Q15700-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DLG2ENST00000376104.7 linkc.2354C>T p.Thr785Ile missense_variant Exon 24 of 28 1 NM_001142699.3 ENSP00000365272.2 Q15700-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152112
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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
GnomAD2 exomes
AF:
0.0000524
AC:
13
AN:
248224
AF XY:
0.0000742
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000116
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1460516
Hom.:
0
Cov.:
30
AF XY:
0.0000303
AC XY:
22
AN XY:
726558
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33410
American (AMR)
AF:
0.00
AC:
0
AN:
44614
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26086
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39670
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86182
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53364
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5764
European-Non Finnish (NFE)
AF:
0.0000315
AC:
35
AN:
1111112
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60314
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.476
Heterozygous variant carriers
0
2
4
5
7
9
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152112
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74298
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41416
American (AMR)
AF:
0.0000656
AC:
1
AN:
15254
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2084
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000644
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.0000662
AC:
8
Asia WGS
AF:
0.000289
AC:
1
AN:
3476
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 18, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2354C>T (p.T785I) alteration is located in exon 24 (coding exon 22) of the DLG2 gene. This alteration results from a C to T substitution at nucleotide position 2354, causing the threonine (T) at amino acid position 785 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
0.47
BayesDel_addAF
Benign
-0.084
T
BayesDel_noAF
Benign
-0.14
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.59
.;D;.;.;.;.;.;T;T;T;T;.;T
Eigen
Benign
0.057
Eigen_PC
Benign
0.17
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.31
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.2
.;M;.;.;.;.;.;.;.;.;.;.;.
PhyloP100
8.0
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-3.9
D;D;D;.;.;D;D;D;D;D;D;D;D
REVEL
Benign
0.19
Sift
Uncertain
0.0020
D;D;D;.;.;D;D;D;D;D;D;T;D
Sift4G
Benign
0.11
T;T;T;.;.;T;T;D;T;T;T;.;.
Polyphen
0.11, 0.46, 0.047, 0.057, 0.0060, 0.24, 0.42
.;B;.;.;.;P;B;B;B;B;B;.;.
Vest4
0.61
MutPred
0.42
.;Gain of sheet (P = 0.0049);.;.;.;.;.;.;.;.;.;.;.;
MVP
0.61
MPC
1.4
ClinPred
0.44
T
GERP RS
5.1
Varity_R
0.60
gMVP
0.91
Mutation Taster
=64/36
polymorphism

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

Other links and lift over

dbSNP: rs777007201; hg19: chr11-83182761; API