rs1008310202

Positions:

chr22-31768826-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_001242896.3(DEPDC5):c.376G>A(p.Ala126Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DEPDC5
NM_001242896.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.60

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 links:

ENSG00000285404 (HGNC:):

ENSG00000285404 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DEPDC5. . Gene score misZ 2.6501 (greater than the threshold 3.09). Trascript score misZ 3.7275 (greater than threshold 3.09). GenCC has associacion of gene with focal epilepsy, Brugada syndrome, epilepsy, familial focal, with variable foci 1, familial focal epilepsy with variable foci, autosomal dominant epilepsy with auditory features, autosomal dominant nocturnal frontal lobe epilepsy.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DEPDC5	NM_001242896.3 linkuse as main transcript	c.376G>A	p.Ala126Thr	missense_variant	7/43	ENST00000651528.2	NP_001229825.1	O75140-10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2 linkuse as main transcript	c.376G>A	p.Ala126Thr	missense_variant	7/43		NM_001242896.3	ENSP00000498382.1		O75140-10
ENSG00000285404	ENST00000646701.1 linkuse as main transcript	c.292G>A	p.Ala98Thr	missense_variant	5/21			ENSP00000496158.1		A0A2R8YF50

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

249026

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135092

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460606

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726624

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial focal epilepsy with variable foci

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 15, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 126 of the DEPDC5 protein (p.Ala126Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DEPDC5-related conditions. ClinVar contains an entry for this variant (Variation ID: 466486). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D;D;D;D;.;D;.;D;D;.;.;.;D;D;.;D;D;D;D

M_CAP

Benign

0.051

MetaRNN

Uncertain

0.46

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.55

N;.;.;N;N;.;.;.;N;N;.;N;.;.;N;.;N;.;N;.;.;N;N;.;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.0

N;.;.;.;.;.;.;.;.;N;.;N;.;.;.;.;N;.;N;.;.;N;N;.;.;.

REVEL

Benign

0.29

Sift

Uncertain

0.016

D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;T;.;D;.;.;D;D;.;.;.

Sift4G

Uncertain

0.035

D;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.;T;.;D;.;.;D;T;.;.;.

Polyphen

0.059, 0.32

.;.;.;.;.;.;.;.;B;B;.;.;.;.;.;.;B;.;B;.;.;.;.;.;.;.

Vest4

0.85

MutPred

0.39

Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);Gain of methylation at K131 (P = 0.0626);.;.;

MVP

0.37

MPC

0.76

ClinPred

0.73

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over