rs61731662

Variant names:

• chr22-31870617-A-G
• rs61731662
• NM_001242896.3:c.3358A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001242896.3(DEPDC5):​c.3358A>G​(p.Met1120Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0218 in 1,576,322 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (40 hom., cov: 33)
  • Exomes 𝑓: 0.022 (399 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0570
• Publications: 12 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=0.0023645163).
• BP6: Variant 22-31870617-A-G is Benign according to our data. Variant chr22-31870617-A-G is described in ClinVar as Benign. ClinVar VariationId is 257661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0233 (3555/152288) while in subpopulation AFR AF = 0.0287 (1194/41556). AF 95% confidence interval is 0.0274. There are 40 homozygotes in GnomAd4. There are 1786 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3555 AD gene.

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.3358A>G	p.Met1120Val	missense	Exon 34 of 43	NP_001229825.1	O75140-10
	DEPDC5	NM_001364318.2		c.3358A>G	p.Met1120Val	missense	Exon 34 of 43	NP_001351247.1	O75140-10
	DEPDC5	NM_001136029.4		c.3331A>G	p.Met1111Val	missense	Exon 34 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.3358A>G	p.Met1120Val	missense	Exon 34 of 43	ENSP00000498382.1	O75140-10
	DEPDC5	ENST00000382112.8	TSL:1	c.3358A>G	p.Met1120Val	missense	Exon 34 of 43	ENSP00000371546.4	O75140-10
	DEPDC5	ENST00000433147.2	TSL:1	c.3274A>G	p.Met1092Val	missense	Exon 33 of 42	ENSP00000410544.2	H0Y770

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3531 AN: 152170 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.0213 AC: 4638 AN: 217906 AF XY: 0.0218

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.00450

Gnomad FIN exome AF: 0.0293

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0217 AC: 30883 AN: 1424034 Hom.: 399 Cov.: 31 AF XY: 0.0219 AC XY: 15495 AN XY: 707340

African (AFR) AF: 0.0286 AC: 905 AN: 31650

American (AMR) AF: 0.0155 AC: 570 AN: 36880

Ashkenazi Jewish (ASJ) AF: 0.0106 AC: 260 AN: 24584

East Asian (EAS) AF: 0.00293 AC: 110 AN: 37566

South Asian (SAS) AF: 0.0265 AC: 2108 AN: 79640

European-Finnish (FIN) AF: 0.0303 AC: 1603 AN: 52978

Middle Eastern (MID) AF: 0.0245 AC: 138 AN: 5632

European-Non Finnish (NFE) AF: 0.0218 AC: 23912 AN: 1096400

Other (OTH) AF: 0.0218 AC: 1277 AN: 58704

GnomAD4 genome AF: 0.0233 AC: 3555 AN: 152288 Hom.: 40 Cov.: 33 AF XY: 0.0240 AC XY: 1786 AN XY: 74476

African (AFR) AF: 0.0287 AC: 1194 AN: 41556

American (AMR) AF: 0.0219 AC: 334 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.00443 AC: 23 AN: 5188

South Asian (SAS) AF: 0.0220 AC: 106 AN: 4824

European-Finnish (FIN) AF: 0.0301 AC: 320 AN: 10616

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0213 AC: 1448 AN: 68026

Other (OTH) AF: 0.0326 AC: 69 AN: 2114

Alfa AF: 0.0218 Hom.: 137

Bravo AF: 0.0234

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.0227 AC: 87

ESP6500EA AF: 0.0240 AC: 199

ExAC AF: 0.0210 AC: 2544

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Familial focal epilepsy with variable foci (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.023
DANN	Benign	0.27
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.057
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.024
Sift	Benign	0.89	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.049
MPC		0.40
ClinPred		0.0014	T
GERP RS		-3.2
Varity_R		0.081
Mutation Taster		=97/3	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: rs61731662; hg19: chr22-32266603; COSMIC: COSV56707734;