chr22-31897540-A-C

Variant names:

• chr22-31897540-A-C
• rs1555933874
• NM_001242896.3:c.4262A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001242896.3(DEPDC5):​c.4262A>C​(p.Glu1421Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.94
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	NM_001242896.3	MANE Select	c.4262A>C	p.Glu1421Ala	missense	Exon 40 of 43	NP_001229825.1
	DEPDC5	NM_001364318.2		c.4262A>C	p.Glu1421Ala	missense	Exon 40 of 43	NP_001351247.1
	DEPDC5	NM_001136029.4		c.4235A>C	p.Glu1412Ala	missense	Exon 40 of 43	NP_001129501.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	ENST00000651528.2	MANE Select	c.4262A>C	p.Glu1421Ala	missense	Exon 40 of 43	ENSP00000498382.1
	DEPDC5	ENST00000382112.8	TSL:1	c.4262A>C	p.Glu1421Ala	missense	Exon 40 of 43	ENSP00000371546.4
	DEPDC5	ENST00000433147.2	TSL:1	c.4178A>C	p.Glu1393Ala	missense	Exon 39 of 42	ENSP00000410544.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Benign	0.011	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		8.9
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	0.57	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	0.75	T
Polyphen		1.0	D
Vest4		0.71
MVP		0.25
MPC		2.6
ClinPred		0.97	D
GERP RS		5.6
PromoterAI		-0.029	Neutral
Varity_R		0.59
Mutation Taster		=20/80	disease causing

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: rs1555933874; hg19: chr22-32293526;