Genetic Variant DEPDC5:p.Val272Ile (chr22-31797646-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001242896.3(DEPDC5):c.814G>A(p.Val272Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,614,010 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V272L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.89

Publications

10 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: 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0087249875).

BP6

Variant 22-31797646-G-A is Benign according to our data. Variant chr22-31797646-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00156 (237/152188) while in subpopulation NFE AF = 0.000897 (61/68004). AF 95% confidence interval is 0.000716. There are 2 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 237 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.814G>A	p.Val272Ile	missense	Exon 13 of 43	NP_001229825.1	O75140-10
DEPDC5	NM_001364318.2		c.814G>A	p.Val272Ile	missense	Exon 13 of 43	NP_001351247.1	O75140-10
DEPDC5	NM_001136029.4		c.814G>A	p.Val272Ile	missense	Exon 13 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.814G>A	p.Val272Ile	missense	Exon 13 of 43	ENSP00000498382.1	O75140-10
DEPDC5	ENST00000382112.8	TSL:1	c.814G>A	p.Val272Ile	missense	Exon 13 of 43	ENSP00000371546.4	O75140-10
DEPDC5	ENST00000433147.2	TSL:1	c.730G>A	p.Val244Ile	missense	Exon 12 of 42	ENSP00000410544.2	H0Y770

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

237

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00221

AC:

551

AN:

249096

AF XY:

0.00206

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.00168

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00119

AC:

1738

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

818

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00195

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0145

AC:

773

AN:

53404

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000752

AC:

836

AN:

1111968

Other (OTH)

AF:

0.00109

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

164

247

329

411

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

150

<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:

0.00156

AC:

237

AN:

152188

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

156

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41526

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0150

AC:

159

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68004

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000909

Hom.:

Bravo

AF:

0.000476

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000969

AC:

ExAC

AF:

0.00254

AC:

307

EpiCase

AF:

0.000436

EpiControl

AF:

0.000830

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Familial focal epilepsy with variable foci (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.7

PhyloP100

7.9

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.74

REVEL

Benign

0.14

Sift

Uncertain

0.024

Sift4G

Benign

0.076

Polyphen

0.74

Vest4

0.35

MVP

0.34

MPC

1.1

ClinPred

0.052

GERP RS

5.0

Varity_R

0.54

Mutation Taster

=93/7

polymorphism

(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