rs61731664

chr22-31838811-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001242896.3(DEPDC5):c.2481G>A(p.Pro827=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 1,613,968 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (16 hom., cov: 32)
  • Exomes 𝑓: 0.018 (272 hom.)
• Consequence: DEPDC5 NM_001242896.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 22-31838811-G-A is Benign according to our data. Variant chr22-31838811-G-A is described in ClinVar as [Benign]. Clinvar id is 238676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-31838811-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0136 (2065/152186) while in subpopulation SAS AF= 0.0197 (95/4826). AF 95% confidence interval is 0.0176. There are 16 homozygotes in gnomad4. There are 1056 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DEPDC5	NM_001242896.3	c.2481G>A	p.Pro827=	synonymous_variant	27/43	ENST00000651528.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DEPDC5	ENST00000651528.2	c.2481G>A	p.Pro827=	synonymous_variant	27/43		NM_001242896.3	P4

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2063 AN: 152068 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0246

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0202

GnomAD3 exomes AF: 0.0168 AC: 4196 AN: 249442 Hom.: 39 AF XY: 0.0175 AC XY: 2365 AN XY: 135304

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00250

Gnomad SAS exome AF: 0.0228

Gnomad FIN exome AF: 0.0237

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0213

GnomAD4 exome AF: 0.0183 AC: 26716 AN: 1461782 Hom.: 272 Cov.: 30 AF XY: 0.0186 AC XY: 13501 AN XY: 727206

Gnomad4 AFR exome AF: 0.00227

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.00953

Gnomad4 EAS exome AF: 0.00212

Gnomad4 SAS exome AF: 0.0225

Gnomad4 FIN exome AF: 0.0245

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.0167

GnomAD4 genome AF: 0.0136 AC: 2065 AN: 152186 Hom.: 16 Cov.: 32 AF XY: 0.0142 AC XY: 1056 AN XY: 74400

Gnomad4 AFR AF: 0.00310

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.0197

Gnomad4 FIN AF: 0.0246

Gnomad4 NFE AF: 0.0184

Gnomad4 OTH AF: 0.0200

Alfa AF: 0.0171 Hom.: 12

Bravo AF: 0.0133

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.0209

EpiControl AF: 0.0208

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2016

This alteration is classified as 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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.034
Dann	Benign	0.80

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: rs61731664; hg19: chr22-32234797; COSMIC: COSV56707714; COSMIC: COSV56707714;