Genetic Variant NM_001242896.3:c.1095T>C (chr22-31804175-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001242896.3(DEPDC5):c.1095T>C(p.Asp365Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,613,836 control chromosomes in the GnomAD database, including 375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 60 hom., cov: 32)

Exomes 𝑓: 0.020 ( 315 hom. )

Consequence

DEPDC5
NM_001242896.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.290

Publications

10 publications found

Variant links:

COSMIC-nc: COSV56707603

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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), 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

DEPDC5 links:

ENSG00000285404 (HGNC:):

ENSG00000285404 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 22-31804175-T-C is Benign according to our data. Variant chr22-31804175-T-C is described in ClinVar as Benign. ClinVar VariationId is 257657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.29 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0251 (3817/152176) while in subpopulation AFR AF = 0.0413 (1716/41520). AF 95% confidence interval is 0.0397. There are 60 homozygotes in GnomAd4. There are 1887 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3817 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001242896.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DEPDC5	NM_001242896.3	MANE Select	c.1095T>C	p.Asp365Asp	synonymous	Exon 16 of 43	NP_001229825.1	O75140-10
DEPDC5	NM_001364318.2		c.1095T>C	p.Asp365Asp	synonymous	Exon 16 of 43	NP_001351247.1	O75140-10
DEPDC5	NM_001136029.4		c.1095T>C	p.Asp365Asp	synonymous	Exon 16 of 43	NP_001129501.1	O75140-9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DEPDC5	ENST00000651528.2	MANE Select	c.1095T>C	p.Asp365Asp	synonymous	Exon 16 of 43	ENSP00000498382.1	O75140-10
DEPDC5	ENST00000382112.8	TSL:1	c.1095T>C	p.Asp365Asp	synonymous	Exon 16 of 43	ENSP00000371546.4	O75140-10
DEPDC5	ENST00000433147.2	TSL:1	c.1011T>C	p.Asp337Asp	synonymous	Exon 15 of 42	ENSP00000410544.2	H0Y770

Frequencies

GnomAD3 genomes

AF:

0.0251

AC:

3812

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0414

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0200

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00386

Gnomad SAS

AF:

0.0211

Gnomad FIN

AF:

0.0246

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0190

Gnomad OTH

AF:

0.0301

GnomAD2 exomes

AF:

0.0201

AC:

5021

AN:

249492

AF XY:

0.0201

show subpopulations

Gnomad AFR exome

AF:

0.0413

Gnomad AMR exome

AF:

0.0167

Gnomad ASJ exome

AF:

0.00993

Gnomad EAS exome

AF:

0.00406

Gnomad FIN exome

AF:

0.0242

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0239

GnomAD4 exome

AF:

0.0197

AC:

28817

AN:

1461660

Hom.:

315

Cov.:

AF XY:

0.0199

AC XY:

14439

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.0423

AC:

1416

AN:

33474

American (AMR)

AF:

0.0172

AC:

767

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00815

AC:

213

AN:

26136

East Asian (EAS)

AF:

0.00280

AC:

111

AN:

39700

South Asian (SAS)

AF:

0.0232

AC:

1997

AN:

86244

European-Finnish (FIN)

AF:

0.0248

AC:

1327

AN:

53420

Middle Eastern (MID)

AF:

0.0234

AC:

135

AN:

5766

European-Non Finnish (NFE)

AF:

0.0195

AC:

21635

AN:

1111804

Other (OTH)

AF:

0.0201

AC:

1216

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

1411

2822

4234

5645

7056

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

832

1664

2496

3328

4160

<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:

0.0251

AC:

3817

AN:

152176

Hom.:

Cov.:

AF XY:

0.0254

AC XY:

1887

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0413

AC:

1716

AN:

41520

American (AMR)

AF:

0.0200

AC:

305

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00720

AC:

AN:

3472

East Asian (EAS)

AF:

0.00386

AC:

AN:

5176

South Asian (SAS)

AF:

0.0216

AC:

104

AN:

4820

European-Finnish (FIN)

AF:

0.0246

AC:

260

AN:

10590

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0190

AC:

1294

AN:

68008

Other (OTH)

AF:

0.0298

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

189

378

567

756

945

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0220

Hom.:

Bravo

AF:

0.0263

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0212

EpiControl

AF:

0.0215

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Familial focal epilepsy with variable foci (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.8

(source)

DANN

Benign

0.49

PhyloP100

0.29

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over