22-31792761-A-G

Variant names:

• chr22-31792761-A-G
• rs368571578
• NM_001242896.3:c.711A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001242896.3(DEPDC5):​c.711A>G​(p.Ile237Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,397,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I237V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0400
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08697611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.711A>G	p.Ile237Met	missense_variant	Exon 12 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.711A>G	p.Ile237Met	missense_variant	Exon 12 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.627A>G	p.Ile209Met	missense_variant	Exon 10 of 21			ENSP00000496158.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397920 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 693820

African (AFR) AF: 0.00 AC: 0 AN: 28782

American (AMR) AF: 0.00 AC: 0 AN: 30044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24616

East Asian (EAS) AF: 0.00 AC: 0 AN: 34820

South Asian (SAS) AF: 0.00 AC: 0 AN: 73322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090074

Other (OTH) AF: 0.00 AC: 0 AN: 57768

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Benign	0.85
DEOGEN2	Benign	0.0	.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;T;.;.;T;T;.;.;T;T;.;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.087	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	0.60	N;.;.;N;N;.;.;N;N;.;N;.;N;.;N;N;.;.;N;N;.;.
PhyloP100		-0.040
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.090	N;.;.;.;.;.;.;.;N;.;N;.;.;.;N;N;.;.;N;N;.;.
REVEL	Benign	0.010
Sift	Benign	0.19	T;.;.;.;.;.;.;.;T;.;T;.;.;.;T;T;.;.;T;T;.;.
Sift4G	Benign	0.22	T;.;.;.;.;.;.;.;T;.;T;.;.;.;T;T;.;.;T;T;.;.
Vest4		0.23
ClinPred		0.21	T
GERP RS		3.0
PromoterAI		0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.079
Mutation Taster		=88/12	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: rs368571578; hg19: chr22-32188747;