rs16989537

Variant names:

• chr22-31837042-C-G
• rs16989537
• NM_001242896.3:c.2241C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-31837042-C-G
• chr22-31837042-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001242896.3(DEPDC5):​c.2241C>G​(p.Leu747Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 1,614,154 control chromosomes in the GnomAD database, including 261 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (119 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (142 hom.)
• Consequence: DEPDC5 NM_001242896.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.61
• Publications: 3 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]

ENSG00000285404 (HGNC:):

RNU6-201P (HGNC:47164): (RNA, U6 small nuclear 201, pseudogene)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.14).
• BP6: Variant 22-31837042-C-G is Benign according to our data. Variant chr22-31837042-C-G is described in ClinVar as Benign. ClinVar VariationId is 414452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0709 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	NM_001242896.3	MANE Select	c.2241C>G	p.Leu747Leu	synonymous	Exon 26 of 43	NP_001229825.1
	DEPDC5	NM_001364318.2		c.2241C>G	p.Leu747Leu	synonymous	Exon 26 of 43	NP_001351247.1
	DEPDC5	NM_001136029.4		c.2214C>G	p.Leu738Leu	synonymous	Exon 26 of 43	NP_001129501.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	ENST00000651528.2	MANE Select	c.2241C>G	p.Leu747Leu	synonymous	Exon 26 of 43	ENSP00000498382.1
	DEPDC5	ENST00000382112.8	TSL:1	c.2241C>G	p.Leu747Leu	synonymous	Exon 26 of 43	ENSP00000371546.4
	DEPDC5	ENST00000433147.2	TSL:1	c.2157C>G	p.Leu719Leu	synonymous	Exon 25 of 42	ENSP00000410544.2

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3454 AN: 152146 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.0731

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00864 AC: 2156 AN: 249566 AF XY: 0.00794

Gnomad AFR exome AF: 0.0753

Gnomad AMR exome AF: 0.00657

Gnomad ASJ exome AF: 0.00467

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00443 AC: 6480 AN: 1461890 Hom.: 142 Cov.: 34 AF XY: 0.00464 AC XY: 3373 AN XY: 727246

African (AFR) AF: 0.0779 AC: 2609 AN: 33480

American (AMR) AF: 0.00664 AC: 297 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00413 AC: 108 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0131 AC: 1126 AN: 86258

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53420

Middle Eastern (MID) AF: 0.0210 AC: 121 AN: 5768

European-Non Finnish (NFE) AF: 0.00159 AC: 1772 AN: 1112008

Other (OTH) AF: 0.00729 AC: 440 AN: 60396

GnomAD4 genome AF: 0.0227 AC: 3464 AN: 152264 Hom.: 119 Cov.: 32 AF XY: 0.0229 AC XY: 1702 AN XY: 74450

African (AFR) AF: 0.0731 AC: 3035 AN: 41534

American (AMR) AF: 0.00902 AC: 138 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4818

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

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00228 AC: 155 AN: 68032

Other (OTH) AF: 0.0147 AC: 31 AN: 2110

Alfa AF: 0.00516 Hom.: 12

Bravo AF: 0.0247

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00397

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.5
DANN	Benign	0.71
PhyloP100		1.6
Mutation Taster		=97/3	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: rs16989537; hg19: chr22-32233028; COSMIC: COSV56708438;