22-31804863-C-T

Variant names:

• chr22-31804863-C-T
• rs41311139
• NM_001242896.3:c.1165C>T

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.1165C>T​(p.Arg389Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,613,738 control chromosomes in the GnomAD database, including 765 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. R389H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (41 hom., cov: 32)
  • Exomes 𝑓: 0.030 (724 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.00
• Publications: 14 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=0.0044102967).
• BP6: Variant 22-31804863-C-T is Benign according to our data. Variant chr22-31804863-C-T is described in ClinVar as Benign. ClinVar VariationId is 238672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0194 (2956/152276) while in subpopulation NFE AF = 0.032 (2177/68012). AF 95% confidence interval is 0.0309. There are 41 homozygotes in GnomAd4. There are 1354 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2956 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.1165C>T	p.Arg389Cys	missense	Exon 17 of 43	NP_001229825.1	O75140-10
	DEPDC5	NM_001364318.2		c.1165C>T	p.Arg389Cys	missense	Exon 17 of 43	NP_001351247.1	O75140-10
	DEPDC5	NM_001136029.4		c.1165C>T	p.Arg389Cys	missense	Exon 17 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.1165C>T	p.Arg389Cys	missense	Exon 17 of 43	ENSP00000498382.1	O75140-10
	DEPDC5	ENST00000382112.8	TSL:1	c.1165C>T	p.Arg389Cys	missense	Exon 17 of 43	ENSP00000371546.4	O75140-10
	DEPDC5	ENST00000433147.2	TSL:1	c.1081C>T	p.Arg361Cys	missense	Exon 16 of 42	ENSP00000410544.2	H0Y770

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2956 AN: 152158 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00574

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0221 AC: 5519 AN: 249426 AF XY: 0.0218

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.0257

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0200

Gnomad NFE exome AF: 0.0306

Gnomad OTH exome AF: 0.0223

GnomAD4 exome AF: 0.0298 AC: 43568 AN: 1461462 Hom.: 724 Cov.: 30 AF XY: 0.0294 AC XY: 21366 AN XY: 727040

African (AFR) AF: 0.00463 AC: 155 AN: 33472

American (AMR) AF: 0.0245 AC: 1094 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 315 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0148 AC: 1273 AN: 86232

European-Finnish (FIN) AF: 0.0208 AC: 1113 AN: 53406

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.0342 AC: 37992 AN: 1111694

Other (OTH) AF: 0.0260 AC: 1570 AN: 60376

GnomAD4 genome AF: 0.0194 AC: 2956 AN: 152276 Hom.: 41 Cov.: 32 AF XY: 0.0182 AC XY: 1354 AN XY: 74472

African (AFR) AF: 0.00573 AC: 238 AN: 41550

American (AMR) AF: 0.0153 AC: 234 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0110 AC: 53 AN: 4822

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0320 AC: 2177 AN: 68012

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0272 Hom.: 238

Bravo AF: 0.0195

TwinsUK AF: 0.0353 AC: 131

ALSPAC AF: 0.0343 AC: 132

ESP6500AA AF: 0.00634 AC: 24

ESP6500EA AF: 0.0350 AC: 289

ExAC AF: 0.0226 AC: 2729

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0294

EpiControl AF: 0.0276

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	0.092
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.052
Sift	Benign	0.16	T
Sift4G	Benign	0.18	T
Polyphen		0.90	P
Vest4		0.16
MPC		0.54
ClinPred		0.013	T
GERP RS		-0.89
Varity_R		0.053
Mutation Taster		=91/9	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: rs41311139; hg19: chr22-32200849; COSMIC: COSV56691655;