22-31837151-G-T

Variant names:

• chr22-31837151-G-T
• rs776885208
• NM_001242896.3:c.2350G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001242896.3(DEPDC5):​c.2350G>T​(p.Asp784Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D784N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DEPDC5 NM_001242896.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.88
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	NM_001242896.3	MANE Select	c.2350G>T	p.Asp784Tyr	missense	Exon 26 of 43	NP_001229825.1	O75140-10
	DEPDC5	NM_001364318.2		c.2350G>T	p.Asp784Tyr	missense	Exon 26 of 43	NP_001351247.1	O75140-10
	DEPDC5	NM_001136029.4		c.2323G>T	p.Asp775Tyr	missense	Exon 26 of 43	NP_001129501.1	O75140-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DEPDC5	ENST00000651528.2	MANE Select	c.2350G>T	p.Asp784Tyr	missense	Exon 26 of 43	ENSP00000498382.1	O75140-10
	DEPDC5	ENST00000382112.8	TSL:1	c.2350G>T	p.Asp784Tyr	missense	Exon 26 of 43	ENSP00000371546.4	O75140-10
	DEPDC5	ENST00000433147.2	TSL:1	c.2266G>T	p.Asp756Tyr	missense	Exon 25 of 42	ENSP00000410544.2	H0Y770

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249074 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.77
MVP		0.16
MPC		1.3
ClinPred		0.94	D
GERP RS		4.5
Varity_R		0.36
Mutation Taster		=38/62	disease causing

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: rs776885208; hg19: chr22-32233137;