chr22-31783910-GTGT-G

Variant names:

• chr22-31783910-GTGT-G
• rs587776974
• NM_001242896.3:c.489_491delGTT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 PM4_Supporting PP5_Moderate

The NM_001242896.3(DEPDC5):​c.489_491delGTT​(p.Phe164del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV003845929: Published functional studies demonstrate a damaging effect, as the variant deregulates mTORC1 inhibition in embryonic mouse neurons (Dawson et al., 2020)". Synonymous variant affecting the same amino acid position (i.e. V163V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DEPDC5 NM_001242896.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 6.99
• Publications: 2 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: 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

ENSG00000285404 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003845929: Published functional studies demonstrate a damaging effect, as the variant deregulates mTORC1 inhibition in embryonic mouse neurons (Dawson et al., 2020)
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001242896.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 22-31783910-GTGT-G is Pathogenic according to our data. Variant chr22-31783910-GTGT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 50821.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	NM_001242896.3	MANE Select	c.489_491delGTT	p.Phe164del	disruptive_inframe_deletion	Exon 9 of 43	NP_001229825.1	O75140-10
	DEPDC5	NM_001364318.2		c.489_491delGTT	p.Phe164del	disruptive_inframe_deletion	Exon 9 of 43	NP_001351247.1	O75140-10
	DEPDC5	NM_001136029.4		c.489_491delGTT	p.Phe164del	disruptive_inframe_deletion	Exon 9 of 43	NP_001129501.1	O75140-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	ENST00000651528.2	MANE Select	c.489_491delGTT	p.Phe164del	disruptive_inframe_deletion	Exon 9 of 43	ENSP00000498382.1	O75140-10
	DEPDC5	ENST00000382112.8	TSL:1	c.489_491delGTT	p.Phe164del	disruptive_inframe_deletion	Exon 9 of 43	ENSP00000371546.4	O75140-10
	DEPDC5	ENST00000433147.2	TSL:1	c.405_407delGTT	p.Phe136del	disruptive_inframe_deletion	Exon 8 of 42	ENSP00000410544.2	H0Y770

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Epilepsy, familial focal, with variable foci 1 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.0
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs587776974; hg19: chr22-32179896;