rs61731667

Variant names:

• chr22-31822741-C-A
• rs61731667
• NM_001242896.3:c.2055C>A

Your query was ambiguous. Multiple possible variants found:

• chr22-31822741-C-A
• chr22-31822741-C-G
• chr22-31822741-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001242896.3(DEPDC5):​c.2055C>A​(p.Phe685Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,614,068 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.014 (16 hom., cov: 32)
  • Exomes 𝑓: 0.018 (272 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.55
• 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: 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 -16 ACMG points.

• BP6: Variant 22-31822741-C-A is Benign according to our data. Variant chr22-31822741-C-A is described in ClinVar as Benign. ClinVar VariationId is 238674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0137 (2081/152276) while in subpopulation SAS AF = 0.0195 (94/4822). AF 95% confidence interval is 0.0176. There are 16 homozygotes in GnomAd4. There are 1063 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2081 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.2055C>A	p.Phe685Leu	missense	Exon 24 of 43	NP_001229825.1
	DEPDC5	NM_001364318.2		c.2055C>A	p.Phe685Leu	missense	Exon 24 of 43	NP_001351247.1
	DEPDC5	NM_001136029.4		c.2055C>A	p.Phe685Leu	missense	Exon 24 of 43	NP_001129501.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	ENST00000651528.2	MANE Select	c.2055C>A	p.Phe685Leu	missense	Exon 24 of 43	ENSP00000498382.1
	DEPDC5	ENST00000382112.8	TSL:1	c.2055C>A	p.Phe685Leu	missense	Exon 24 of 43	ENSP00000371546.4
	DEPDC5	ENST00000433147.2	TSL:1	c.1971C>A	p.Phe657Leu	missense	Exon 23 of 42	ENSP00000410544.2

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2079 AN: 152160 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0246

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0169 AC: 4221 AN: 249294 AF XY: 0.0176

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00401

Gnomad FIN exome AF: 0.0237

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0183 AC: 26751 AN: 1461792 Hom.: 272 Cov.: 30 AF XY: 0.0186 AC XY: 13508 AN XY: 727186

African (AFR) AF: 0.00227 AC: 76 AN: 33480

American (AMR) AF: 0.0133 AC: 594 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00957 AC: 250 AN: 26134

East Asian (EAS) AF: 0.00275 AC: 109 AN: 39700

South Asian (SAS) AF: 0.0224 AC: 1934 AN: 86232

European-Finnish (FIN) AF: 0.0245 AC: 1307 AN: 53404

Middle Eastern (MID) AF: 0.0196 AC: 113 AN: 5768

European-Non Finnish (NFE) AF: 0.0192 AC: 21352 AN: 1111958

Other (OTH) AF: 0.0168 AC: 1016 AN: 60392

GnomAD4 genome AF: 0.0137 AC: 2081 AN: 152276 Hom.: 16 Cov.: 32 AF XY: 0.0143 AC XY: 1063 AN XY: 74448

African (AFR) AF: 0.00313 AC: 130 AN: 41572

American (AMR) AF: 0.0145 AC: 222 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3468

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5188

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4822

European-Finnish (FIN) AF: 0.0246 AC: 261 AN: 10608

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0185 AC: 1256 AN: 68022

Other (OTH) AF: 0.0204 AC: 43 AN: 2108

Alfa AF: 0.0171 Hom.: 86

Bravo AF: 0.0133

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.00329 AC: 13

ESP6500EA AF: 0.0203 AC: 169

ExAC AF: 0.0165 AC: 1991

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0209

EpiControl AF: 0.0207

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	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	0.33
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.014	T
Eigen	Benign	0.0088
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.062
Sift	Benign	0.58	T
Sift4G	Benign	0.76	T
Polyphen		0.065	B
Vest4		0.35
MutPred		0.14		Loss of catalytic residue at F685 (P = 0.0983)
MPC		0.50
ClinPred		0.011	T
GERP RS		4.3
Varity_R		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: -48

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61731667; hg19: chr22-32218727; COSMIC: COSV56707650; COSMIC: COSV56707650;