rs587777459

Variant names:

• chr22-31815005-C-G
• rs587777459
• NM_001242896.3:c.1459C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-31815005-C-G
• chr22-31815005-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_001242896.3(DEPDC5):​c.1459C>G​(p.Arg487Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R487Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27
• Publications: 6 publications found

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

ENSG00000285404 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10192931).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.1459C>G	p.Arg487Gly	missense_variant	Exon 21 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.1459C>G	p.Arg487Gly	missense_variant	Exon 21 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.1375C>G	p.Arg459Gly	missense_variant	Exon 19 of 21			ENSP00000496158.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249258 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111910

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial focal epilepsy with variable foci Uncertain:1

Jan 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1044457). This variant has not been reported in the literature in individuals affected with DEPDC5-related conditions. This variant is present in population databases (rs587777459, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 487 of the DEPDC5 protein (p.Arg487Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.0041
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;.;.;D;D;.;.;D;D;.;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.;L;L;.;.;L;L;.;L;.;L;.;L;L;.;.;L;L;.;.
PhyloP100		2.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N;.;.;.;.;.;.;.;N;.;N;.;.;.;N;N;.;.;N;N;.;.
REVEL	Benign	0.084
Sift	Benign	0.042	D;.;.;.;.;.;.;.;T;.;D;.;.;.;D;T;.;.;D;T;.;.
Sift4G	Benign	0.43	T;.;.;.;.;.;.;.;T;.;T;.;.;.;T;T;.;.;T;T;.;.
Polyphen		0.31, 0.0	.;.;.;.;.;.;.;B;B;.;.;.;.;.;B;B;.;.;.;.;.;.
Vest4		0.28
MutPred		0.22		Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);.;Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);.;Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);.;Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);Loss of MoRF binding (P = 0.0517);.;.;
MVP		0.15
MPC		0.56
ClinPred		0.50	T
GERP RS		5.1
Varity_R		0.14
Mutation Taster		=69/31	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

Other links and lift over

dbSNP: rs587777459; hg19: chr22-32210991;