chr18-45858590-T-G

Variant names:

• chr18-45858590-T-G
• rs137887553
• NM_020964.3:c.7202A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020964.3(EPG5):​c.7202A>C​(p.Lys2401Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. K2401R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86
• Publications: 1 publications found

Genes affected

EPG5 (HGNC:29331): (ectopic P-granules 5 autophagy tethering factor) This gene encodes a large coiled coil domain-containing protein that functions in autophagy during starvation conditions. Mutations in this gene cause Vici syndrome. [provided by RefSeq, Aug 2015]

EPG5 Gene-Disease associations (from GenCC):

• Vici syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08684033).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020964.3. 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
	EPG5	NM_020964.3	MANE Select	c.7202A>C	p.Lys2401Thr	missense	Exon 41 of 44	NP_066015.2
	EPG5	NM_001410859.1		c.7199A>C	p.Lys2400Thr	missense	Exon 41 of 44	NP_001397788.1
	EPG5	NM_001410858.1		c.7202A>C	p.Lys2401Thr	missense	Exon 41 of 44	NP_001397787.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	ENST00000282041.11	TSL:1 MANE Select	c.7202A>C	p.Lys2401Thr	missense	Exon 41 of 44	ENSP00000282041.4
	EPG5	ENST00000587884.2	TSL:1	n.*2942A>C		non_coding_transcript_exon	Exon 42 of 45	ENSP00000466990.2
	EPG5	ENST00000590884.6	TSL:1	n.*1514A>C		non_coding_transcript_exon	Exon 39 of 42	ENSP00000466403.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.042
Sift	Benign	0.38	T
Sift4G	Benign	0.33	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.38		Loss of ubiquitination at K2401 (P = 0.0199)
MVP		0.17
MPC		0.18
ClinPred		0.075	T
GERP RS		-0.36
Varity_R		0.041
gMVP		0.14

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: rs137887553; hg19: chr18-43438555;