rs144712084

Variant names:

• chr22-31765043-A-G
• rs144712084
• NM_001242896.3:c.262A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-31765043-A-G
• chr22-31765043-A-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001242896.3(DEPDC5):​c.262A>G​(p.Asn88Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,613,846 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00095 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 9.10
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013042808).
• BP6: Variant 22-31765043-A-G is Benign according to our data. Variant chr22-31765043-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 466473.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000952 (145/152282) while in subpopulation AFR AF = 0.00337 (140/41550). AF 95% confidence interval is 0.00291. There are 1 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 145 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.262A>G	p.Asn88Asp	missense	Exon 5 of 43	NP_001229825.1	O75140-10
	DEPDC5	NM_001364318.2		c.262A>G	p.Asn88Asp	missense	Exon 5 of 43	NP_001351247.1	O75140-10
	DEPDC5	NM_001136029.4		c.262A>G	p.Asn88Asp	missense	Exon 5 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.262A>G	p.Asn88Asp	missense	Exon 5 of 43	ENSP00000498382.1	O75140-10
	DEPDC5	ENST00000382112.8	TSL:1	c.262A>G	p.Asn88Asp	missense	Exon 5 of 43	ENSP00000371546.4	O75140-10
	DEPDC5	ENST00000433147.2	TSL:1	c.262A>G	p.Asn88Asp	missense	Exon 5 of 42	ENSP00000410544.2	H0Y770

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000212 AC: 53 AN: 249500 AF XY: 0.000148

Gnomad AFR exome AF: 0.00336

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1461564 Hom.: 0 Cov.: 29 AF XY: 0.0000825 AC XY: 60 AN XY: 727096

African (AFR) AF: 0.00391 AC: 131 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111722

Other (OTH) AF: 0.000215 AC: 13 AN: 60390

GnomAD4 genome AF: 0.000952 AC: 145 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74472

African (AFR) AF: 0.00337 AC: 140 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000308 Hom.: 0

Bravo AF: 0.00116

ESP6500AA AF: 0.00366 AC: 14

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000298 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	DEPDC5-related disorder (1)
-	1	-	Epilepsy, familial focal, with variable foci 1 (1)
-	-	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	0.25
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.23
Sift	Benign	0.12	T
Sift4G	Benign	0.086	T
Polyphen		0.96	D
Vest4		0.80
MVP		0.48
MPC		1.3
ClinPred		0.12	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
Mutation Taster		=46/54	disease causing

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: rs144712084; hg19: chr22-32161029;