rs566255762

Variant names:

• chr22-31906501-C-CAGGCTGCACCAGGGTTAGA
• rs566255762
• ENST00000400246.7:n.*1090_*1091insAGGGTTAGAAGGCTGCACC

Variant summary

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

The ENST00000400246.7(DEPDC5):​n.*1090_*1091insAGGGTTAGAAGGCTGCACC variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,612,724 control chromosomes in the GnomAD database, including 322 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (19 hom., cov: 32)
  • Exomes 𝑓: 0.019 (303 hom.)
• Consequence: DEPDC5 ENST00000400246.7 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.30
• Publications: 1 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 22-31906501-C-CAGGCTGCACCAGGGTTAGA is Benign according to our data. Variant chr22-31906501-C-CAGGCTGCACCAGGGTTAGA is described in ClinVar as Benign. ClinVar VariationId is 257656.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 = 0.0143 (2181/152360) while in subpopulation SAS AF = 0.0207 (100/4822). AF 95% confidence interval is 0.0182. There are 19 homozygotes in GnomAd4. There are 1115 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2181 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.*14_*15insAGGGTTAGAAGGCTGCACC		3_prime_UTR_variant	Exon 43 of 43	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.*14_*15insAGGGTTAGAAGGCTGCACC		3_prime_UTR_variant	Exon 43 of 43		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.1787-49628_1787-49627insAGGGTTAGAAGGCTGCACC		intron_variant	Intron 20 of 20			ENSP00000496158.1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2177 AN: 152242 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00442

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0249

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.0248

GnomAD2 exomes AF: 0.0176 AC: 4368 AN: 247912 AF XY: 0.0184

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00423

Gnomad FIN exome AF: 0.0234

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0192 AC: 28030 AN: 1460364 Hom.: 303 Cov.: 32 AF XY: 0.0195 AC XY: 14157 AN XY: 726258

African (AFR) AF: 0.00296 AC: 99 AN: 33464

American (AMR) AF: 0.0137 AC: 613 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00946 AC: 247 AN: 26118

East Asian (EAS) AF: 0.00287 AC: 114 AN: 39676

South Asian (SAS) AF: 0.0252 AC: 2176 AN: 86238

European-Finnish (FIN) AF: 0.0243 AC: 1287 AN: 52868

Middle Eastern (MID) AF: 0.0212 AC: 122 AN: 5756

European-Non Finnish (NFE) AF: 0.0201 AC: 22307 AN: 1111178

Other (OTH) AF: 0.0176 AC: 1065 AN: 60356

GnomAD4 genome AF: 0.0143 AC: 2181 AN: 152360 Hom.: 19 Cov.: 32 AF XY: 0.0150 AC XY: 1115 AN XY: 74512

African (AFR) AF: 0.00341 AC: 142 AN: 41598

American (AMR) AF: 0.0159 AC: 244 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00443 AC: 23 AN: 5190

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4822

European-Finnish (FIN) AF: 0.0249 AC: 265 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0191 AC: 1300 AN: 68022

Other (OTH) AF: 0.0246 AC: 52 AN: 2116

Alfa AF: 0.0159 Hom.: 5

Bravo AF: 0.0132

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 05, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs566255762; hg19: chr22-32302487; COSMIC: COSV56707779;