rs59422275

Variant names:

• chr18-45954858-T-C
• rs59422275
• NM_020964.3:c.544A>G

Variant summary

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

The NM_020964.3(EPG5):​c.544A>G​(p.Lys182Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0857 in 1,614,110 control chromosomes in the GnomAD database, including 7,085 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. K182K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1362 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5723 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.10
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038298368).
• BP6: Variant 18-45954858-T-C is Benign according to our data. Variant chr18-45954858-T-C is described in ClinVar as Benign. ClinVar VariationId is 402834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	NM_020964.3	MANE Select	c.544A>G	p.Lys182Glu	missense	Exon 2 of 44	NP_066015.2
	EPG5	NM_001410859.1		c.544A>G	p.Lys182Glu	missense	Exon 2 of 44	NP_001397788.1
	EPG5	NM_001410858.1		c.544A>G	p.Lys182Glu	missense	Exon 2 of 44	NP_001397787.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	ENST00000282041.11	TSL:1 MANE Select	c.544A>G	p.Lys182Glu	missense	Exon 2 of 44	ENSP00000282041.4
	EPG5	ENST00000587884.2	TSL:1	n.544A>G		non_coding_transcript_exon	Exon 2 of 45	ENSP00000466990.2
	EPG5	ENST00000587974.1	TSL:1	n.579A>G		non_coding_transcript_exon	Exon 2 of 24

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17605 AN: 152180 Hom.: 1358 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0778

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0239

Gnomad SAS AF: 0.0766

Gnomad FIN AF: 0.0439

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0835

Gnomad OTH AF: 0.0989

GnomAD2 exomes AF: 0.0845 AC: 21063 AN: 249294 AF XY: 0.0833

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.0778

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0233

Gnomad FIN exome AF: 0.0490

Gnomad NFE exome AF: 0.0802

Gnomad OTH exome AF: 0.0848

GnomAD4 exome AF: 0.0826 AC: 120703 AN: 1461812 Hom.: 5723 Cov.: 32 AF XY: 0.0825 AC XY: 59982 AN XY: 727210

African (AFR) AF: 0.219 AC: 7341 AN: 33468

American (AMR) AF: 0.0780 AC: 3486 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3255 AN: 26136

East Asian (EAS) AF: 0.0207 AC: 822 AN: 39698

South Asian (SAS) AF: 0.0859 AC: 7412 AN: 86246

European-Finnish (FIN) AF: 0.0487 AC: 2599 AN: 53420

Middle Eastern (MID) AF: 0.104 AC: 600 AN: 5766

European-Non Finnish (NFE) AF: 0.0809 AC: 89913 AN: 1111972

Other (OTH) AF: 0.0874 AC: 5275 AN: 60386

GnomAD4 genome AF: 0.116 AC: 17618 AN: 152298 Hom.: 1362 Cov.: 33 AF XY: 0.112 AC XY: 8319 AN XY: 74458

African (AFR) AF: 0.218 AC: 9075 AN: 41548

American (AMR) AF: 0.0777 AC: 1189 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 425 AN: 3466

East Asian (EAS) AF: 0.0236 AC: 122 AN: 5178

South Asian (SAS) AF: 0.0766 AC: 370 AN: 4828

European-Finnish (FIN) AF: 0.0439 AC: 466 AN: 10620

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0835 AC: 5678 AN: 68028

Other (OTH) AF: 0.0974 AC: 206 AN: 2114

Alfa AF: 0.0929 Hom.: 2614

Bravo AF: 0.123

TwinsUK AF: 0.0736 AC: 273

ALSPAC AF: 0.0734 AC: 283

ESP6500AA AF: 0.203 AC: 784

ESP6500EA AF: 0.0832 AC: 687

ExAC AF: 0.0872 AC: 10530

Asia WGS AF: 0.0610 AC: 210 AN: 3478

EpiCase AF: 0.0840

EpiControl AF: 0.0848

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.5
DANN	Benign	0.92
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.1
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.039
Sift	Benign	0.51	T
Sift4G	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.065
MPC		0.21
ClinPred		0.0032	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.19
Mutation Taster		=98/2	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: rs59422275; hg19: chr18-43534824; COSMIC: COSV56346706;