rs759952667

Positions:

• chr22-31797697-C-A
• chr22-31797697-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001242896.3(DEPDC5):​c.865C>A​(p.Gln289Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.52

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10140687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.865C>A	p.Gln289Lys	missense_variant	13/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.865C>A	p.Gln289Lys	missense_variant	13/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459846 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726362

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.12	.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;.;.;D;D;.;.;D;D;.;D;D;D
M_CAP	Benign	0.012	T
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	-1.1	T
MutationAssessor	Benign	-0.15	N;.;.;N;N;.;.;N;N;.;N;.;N;.;N;N;.;.;N;N;.;.
MutationTaster	Benign	0.89	D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N;.;.;.;.;.;.;.;N;.;N;.;.;.;N;N;.;.;N;N;.;.
REVEL	Benign	0.028
Sift	Benign	0.43	T;.;.;.;.;.;.;.;T;.;T;.;.;.;T;T;.;.;T;T;.;.
Sift4G	Benign	0.39	T;.;.;.;.;.;.;.;T;.;T;.;.;.;T;T;.;.;T;T;.;.
Polyphen		0.0, 0.0090	.;.;.;.;.;.;.;B;B;.;.;.;.;.;B;B;.;.;.;.;.;.
Vest4		0.36
MutPred		0.42		Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);.;Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);.;Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);.;Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);Gain of ubiquitination at Q289 (P = 0.0082);.;
MVP		0.19
MPC		0.53
ClinPred		0.68	D
GERP RS		5.0
Varity_R		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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

Other links and lift over

dbSNP: rs759952667; hg19: chr22-32193683;