22-31879956-C-T

Variant names:

• chr22-31879956-C-T
• rs16989600
• NM_001242896.3:c.4033+204C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001242896.3(DEPDC5):​c.4033+204C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0659 in 579,228 control chromosomes in the GnomAD database, including 1,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.081 (569 hom., cov: 32)
  • Exomes 𝑓: 0.061 (973 hom.)
• Consequence: DEPDC5 NM_001242896.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0840
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 22-31879956-C-T is Benign according to our data. Variant chr22-31879956-C-T is described in ClinVar as Benign. ClinVar VariationId is 1269081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DEPDC5	NM_001242896.3	c.4033+204C>T		intron_variant	Intron 38 of 42	ENST00000651528.2	NP_001229825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DEPDC5	ENST00000651528.2	c.4033+204C>T		intron_variant	Intron 38 of 42		NM_001242896.3	ENSP00000498382.1
ENSG00000285404	ENST00000646701.1	c.1786+60731C>T		intron_variant	Intron 20 of 20			ENSP00000496158.1

Frequencies

GnomAD3 genomes AF: 0.0808 AC: 12281 AN: 152040 Hom.: 563 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0586

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.0405

Gnomad FIN AF: 0.0763

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0582

Gnomad OTH AF: 0.0755

GnomAD4 exome AF: 0.0606 AC: 25883 AN: 427070 Hom.: 973 Cov.: 4 AF XY: 0.0588 AC XY: 13230 AN XY: 224994

African (AFR) AF: 0.119 AC: 1421 AN: 11986

American (AMR) AF: 0.138 AC: 2507 AN: 18194

Ashkenazi Jewish (ASJ) AF: 0.0600 AC: 778 AN: 12966

East Asian (EAS) AF: 0.0205 AC: 590 AN: 28748

South Asian (SAS) AF: 0.0420 AC: 1927 AN: 45830

European-Finnish (FIN) AF: 0.0814 AC: 2198 AN: 27018

Middle Eastern (MID) AF: 0.0557 AC: 102 AN: 1830

European-Non Finnish (NFE) AF: 0.0577 AC: 14773 AN: 255964

Other (OTH) AF: 0.0647 AC: 1587 AN: 24534

GnomAD4 genome AF: 0.0809 AC: 12310 AN: 152158 Hom.: 569 Cov.: 32 AF XY: 0.0801 AC XY: 5961 AN XY: 74396

African (AFR) AF: 0.118 AC: 4882 AN: 41512

American (AMR) AF: 0.119 AC: 1813 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0586 AC: 203 AN: 3466

East Asian (EAS) AF: 0.0280 AC: 145 AN: 5172

South Asian (SAS) AF: 0.0400 AC: 193 AN: 4830

European-Finnish (FIN) AF: 0.0763 AC: 807 AN: 10582

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0582 AC: 3962 AN: 68018

Other (OTH) AF: 0.0752 AC: 159 AN: 2114

Alfa AF: 0.0859 Hom.: 136

Bravo AF: 0.0864

Asia WGS AF: 0.0600 AC: 207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.6
DANN	Benign	0.90
PhyloP100		-0.084
Mutation Taster		=99/1	polymorphism (auto)

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: rs16989600; hg19: chr22-32275942;