rs5998126

Variant names:

• chr22-31782416-T-C
• rs5998126
• NM_001242896.3:c.484-1491T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001242896.3(DEPDC5):​c.484-1491T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 152,060 control chromosomes in the GnomAD database, including 9,434 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.33 (9434 hom., cov: 32)
• Consequence: DEPDC5 NM_001242896.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.749
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

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.484-1491T>C		intron	N/A	NP_001229825.1
	DEPDC5	NM_001364318.2		c.484-1491T>C		intron	N/A	NP_001351247.1
	DEPDC5	NM_001136029.4		c.484-1491T>C		intron	N/A	NP_001129501.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	ENST00000651528.2	MANE Select	c.484-1491T>C		intron	N/A	ENSP00000498382.1
	DEPDC5	ENST00000382112.8	TSL:1	c.484-1491T>C		intron	N/A	ENSP00000371546.4
	DEPDC5	ENST00000433147.2	TSL:1	c.400-1491T>C		intron	N/A	ENSP00000410544.2

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49955 AN: 151942 Hom.: 9396 Cov.: 32

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.271

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.301

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

GnomAD4 genome AF: 0.329 AC: 50042 AN: 152060 Hom.: 9434 Cov.: 32 AF XY: 0.329 AC XY: 24474 AN XY: 74306

African (AFR) AF: 0.527 AC: 21878 AN: 41502

American (AMR) AF: 0.287 AC: 4384 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 672 AN: 3468

East Asian (EAS) AF: 0.199 AC: 1025 AN: 5152

South Asian (SAS) AF: 0.336 AC: 1622 AN: 4826

European-Finnish (FIN) AF: 0.283 AC: 2991 AN: 10556

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.243 AC: 16513 AN: 67972

Other (OTH) AF: 0.299 AC: 630 AN: 2110

Alfa AF: 0.298 Hom.: 911

Bravo AF: 0.338

Asia WGS AF: 0.317 AC: 1105 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.23
DANN	Benign	0.47
PhyloP100		-0.75
Mutation Taster		=100/0	polymorphism (auto)

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: rs5998126; hg19: chr22-32178402;