22-31838816-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001242896.3(DEPDC5):​c.2486C>G​(p.Pro829Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P829L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

1
11
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.43

Publications

0 publications found
Variant links:
Genes affected
DEPDC5 (HGNC:18423): (DEP domain containing 5, GATOR1 subcomplex subunit) This gene encodes a member of the IML1 family of proteins involved in G-protein signaling pathways. The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth by sensing the availability of nutrients. The protein encoded by this gene is a component of the GATOR1 (GAP activity toward Rags) complex which inhibits the amino acid-sensing branch of the mTORC1 pathway. Mutations in this gene are associated with autosomal dominant familial focal epilepsy with variable foci. A single nucleotide polymorphism in an intron of this gene has been associated with an increased risk of hepatocellular carcinoma in individuals with chronic hepatitis C virus infection. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]
DEPDC5 Gene-Disease associations (from GenCC):
  • epilepsy, familial focal, with variable foci 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Illumina, G2P
  • focal epilepsy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • autosomal dominant epilepsy with auditory features
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal dominant nocturnal frontal lobe epilepsy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial focal epilepsy with variable foci
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Brugada syndrome
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
DEPDC5NM_001242896.3 linkc.2486C>G p.Pro829Arg missense_variant Exon 27 of 43 ENST00000651528.2 NP_001229825.1 O75140-10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DEPDC5ENST00000651528.2 linkc.2486C>G p.Pro829Arg missense_variant Exon 27 of 43 NM_001242896.3 ENSP00000498382.1 O75140-10
ENSG00000285404ENST00000646701.1 linkc.1786+19591C>G intron_variant Intron 20 of 20 ENSP00000496158.1 A0A2R8YF50

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461776
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727196
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86244
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111930
Other (OTH)
AF:
0.00
AC:
0
AN:
60390
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Uncertain
0.092
D
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
.;.;.;.;.;T;.;.;.;.;T;.;.;.;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;.;.;D;D;.;D;.;D;D
M_CAP
Benign
0.033
D
MetaRNN
Uncertain
0.60
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
.;.;M;.;.;M;.;.;.;.;M;.;M;M;.
PhyloP100
7.4
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-2.5
N;.;.;.;.;.;N;.;.;.;D;.;.;D;.
REVEL
Benign
0.18
Sift
Benign
0.040
D;.;.;.;.;.;D;.;.;.;T;.;.;T;.
Sift4G
Uncertain
0.038
D;.;.;.;.;.;D;.;.;.;D;.;.;D;.
Polyphen
1.0
.;.;D;.;.;.;.;.;.;.;.;.;D;.;.
Vest4
0.52
MVP
0.093
MPC
1.1
ClinPred
0.95
D
GERP RS
5.7
Varity_R
0.33
Mutation Taster
=33/67
disease causing

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: rs370487077; hg19: chr22-32234802; API