rs201464790

Positions:

• chr22-31822758-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001242896.3(DEPDC5):​c.2072T>C​(p.Leu691Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,614,124 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.09

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DEPDC5
• BP4: Computational evidence support a benign effect (MetaRNN=0.002968043).
• BP6: Variant 22-31822758-T-C is Benign according to our data. Variant chr22-31822758-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 414472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31822758-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00211 (322/152304) while in subpopulation AFR AF= 0.00717 (298/41556). AF 95% confidence interval is 0.0065. There are 2 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.2072T>C	p.Leu691Pro	missense_variant	24/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.2072T>C	p.Leu691Pro	missense_variant	24/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 320 AN: 152186 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00714

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000670 AC: 167 AN: 249268 Hom.: 0 AF XY: 0.000414 AC XY: 56 AN XY: 135254

Gnomad AFR exome AF: 0.00885

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000233 AC: 341 AN: 1461820 Hom.: 0 Cov.: 30 AF XY: 0.000194 AC XY: 141 AN XY: 727202

Gnomad4 AFR exome AF: 0.00797

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152304 Hom.: 2 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74466

Gnomad4 AFR AF: 0.00717

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.00210

ExAC AF: 0.000744 AC: 90

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	DEPDC5: BS1, BS2 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial focal epilepsy with variable foci Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	0.082
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;.;D;D;.;D;.;D;D
MetaRNN	Benign	0.0030	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
Polyphen		0.0070, 0.41	.;.;B;.;B;.;.;.;B;.;B;.;.
Vest4		0.59, 0.56, 0.45, 0.55, 0.45
MVP		0.13
MPC		1.2
ClinPred		0.021	T
GERP RS		5.4
Varity_R		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs201464790; hg19: chr22-32218744;