22-31822705-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001242896.3(DEPDC5):​c.2019C>G​(p.Ser673Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,964 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S673S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

DEPDC5
NM_001242896.3 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.303

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: Benign. The variant received -19 ACMG points.

BP4
Computational evidence support a benign effect (REVEL=0.069).
BP6
Variant 22-31822705-C-G is Benign according to our data. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822705-C-G is described in CliVar as Likely_benign. Clinvar id is 534819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.303 with no splicing effect.
BS1
Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000554 (81/1461774) while in subpopulation MID AF = 0.00104 (6/5760). AF 95% confidence interval is 0.000453. There are 0 homozygotes in GnomAdExome4. There are 40 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
BS2
High AC in GnomAdExome4 at 81 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DEPDC5NM_001242896.3 linkc.2019C>G p.Ser673Ser synonymous_variant Exon 24 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.2019C>G p.Ser673Ser synonymous_variant Exon 24 of 43 NM_001242896.3 ENSP00000498382.1 O75140-10
ENSG00000285404ENST00000646701.1 linkc.1786+3480C>G intron_variant Intron 20 of 20 ENSP00000496158.1 A0A2R8YF50

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000562
AC:
14
AN:
249144
AF XY:
0.0000666
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000174
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000620
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000554
AC:
81
AN:
1461774
Hom.:
0
Cov.:
30
AF XY:
0.0000550
AC XY:
40
AN XY:
727174
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.000179
AC:
8
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86240
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53406
Middle Eastern (MID)
AF:
0.00104
AC:
6
AN:
5760
European-Non Finnish (NFE)
AF:
0.0000585
AC:
65
AN:
1111954
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.453
Heterozygous variant carriers
0
4
8
13
17
21
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
152190
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74336
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41454
American (AMR)
AF:
0.0000655
AC:
1
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4812
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68046
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000302
EpiCase
AF:
0.000164
EpiControl
AF:
0.000237

ClinVar

Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Sep 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 06, 2019
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Benign:1
Jan 31, 2017
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial focal epilepsy with variable foci Benign:1
Oct 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.36
CADD
Benign
7.0
DANN
Benign
0.73
PhyloP100
0.30
Mutation Taster
=99/1
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: rs372975881; hg19: chr22-32218691; API