rs16989528

Variant names:

• chr22-31821553-C-T
• rs16989528
• NM_001242896.3:c.1922C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-31821553-C-T
• chr22-31821553-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001242896.3(DEPDC5):​c.1922C>T​(p.Ala641Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,614,110 control chromosomes in the GnomAD database, including 1,125 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A641T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (99 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1026 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.08
• Publications: 17 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001611352).
• BP6: Variant 22-31821553-C-T is Benign according to our data. Variant chr22-31821553-C-T is described in ClinVar as Benign. ClinVar VariationId is 257659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0576 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	NM_001242896.3	MANE Select	c.1922C>T	p.Ala641Val	missense	Exon 23 of 43	NP_001229825.1	O75140-10
	DEPDC5	NM_001364318.2		c.1922C>T	p.Ala641Val	missense	Exon 23 of 43	NP_001351247.1	O75140-10
	DEPDC5	NM_001136029.4		c.1922C>T	p.Ala641Val	missense	Exon 23 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.1922C>T	p.Ala641Val	missense	Exon 23 of 43	ENSP00000498382.1	O75140-10
	DEPDC5	ENST00000382112.8	TSL:1	c.1922C>T	p.Ala641Val	missense	Exon 23 of 43	ENSP00000371546.4	O75140-10
	DEPDC5	ENST00000433147.2	TSL:1	c.1838C>T	p.Ala613Val	missense	Exon 22 of 42	ENSP00000410544.2	H0Y770

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4342 AN: 152180 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.0225

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.0855

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0342

Gnomad OTH AF: 0.0311

GnomAD2 exomes AF: 0.0348 AC: 8664 AN: 249060 AF XY: 0.0372

Gnomad AFR exome AF: 0.00555

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0236

Gnomad EAS exome AF: 0.0201

Gnomad FIN exome AF: 0.0802

Gnomad NFE exome AF: 0.0346

Gnomad OTH exome AF: 0.0322

GnomAD4 exome AF: 0.0344 AC: 50347 AN: 1461812 Hom.: 1026 Cov.: 31 AF XY: 0.0352 AC XY: 25585 AN XY: 727196

African (AFR) AF: 0.00499 AC: 167 AN: 33480

American (AMR) AF: 0.0155 AC: 691 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 673 AN: 26136

East Asian (EAS) AF: 0.0264 AC: 1047 AN: 39700

South Asian (SAS) AF: 0.0562 AC: 4843 AN: 86250

European-Finnish (FIN) AF: 0.0760 AC: 4059 AN: 53412

Middle Eastern (MID) AF: 0.0342 AC: 197 AN: 5768

European-Non Finnish (NFE) AF: 0.0330 AC: 36643 AN: 1111950

Other (OTH) AF: 0.0336 AC: 2027 AN: 60392

GnomAD4 genome AF: 0.0285 AC: 4341 AN: 152298 Hom.: 99 Cov.: 32 AF XY: 0.0320 AC XY: 2384 AN XY: 74460

African (AFR) AF: 0.00520 AC: 216 AN: 41574

American (AMR) AF: 0.0221 AC: 338 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3470

East Asian (EAS) AF: 0.0224 AC: 116 AN: 5186

South Asian (SAS) AF: 0.0634 AC: 306 AN: 4826

European-Finnish (FIN) AF: 0.0855 AC: 906 AN: 10598

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0342 AC: 2327 AN: 68026

Other (OTH) AF: 0.0303 AC: 64 AN: 2112

Alfa AF: 0.0302 Hom.: 205

Bravo AF: 0.0215

TwinsUK AF: 0.0272 AC: 101

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00541 AC: 22

ESP6500EA AF: 0.0295 AC: 247

ExAC AF: 0.0357 AC: 4312

Asia WGS AF: 0.0360 AC: 128 AN: 3478

EpiCase AF: 0.0356

EpiControl AF: 0.0326

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Familial focal epilepsy with variable foci (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.025
Sift	Benign	0.13	T
Sift4G	Benign	0.33	T
Polyphen		0.061	B
Vest4		0.093
MPC		0.40
ClinPred		0.011	T
GERP RS		0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
Mutation Taster		=98/2	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: rs16989528; hg19: chr22-32217539; COSMIC: COSV56700799; COSMIC: COSV56700799;