2-148753927-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_015630.4(EPC2):​c.460C>T​(p.Leu154Phe) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

EPC2
NM_015630.4 missense, splice_region

Scores

4
4
11
Splicing: ADA: 0.9965
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.00
Variant links:
Genes affected
EPC2 (HGNC:24543): (enhancer of polycomb homolog 2) Predicted to contribute to histone acetyltransferase activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of Piccolo NuA4 histone acetyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EPC2NM_015630.4 linkc.460C>T p.Leu154Phe missense_variant, splice_region_variant Exon 4 of 14 ENST00000258484.11 NP_056445.3 Q52LR7
EPC2XM_011510941.3 linkc.460C>T p.Leu154Phe missense_variant, splice_region_variant Exon 4 of 14 XP_011509243.1
EPC2XM_011510943.4 linkc.193C>T p.Leu65Phe missense_variant, splice_region_variant Exon 3 of 13 XP_011509245.1
EPC2XM_047443897.1 linkc.112C>T p.Leu38Phe missense_variant, splice_region_variant Exon 3 of 13 XP_047299853.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EPC2ENST00000258484.11 linkc.460C>T p.Leu154Phe missense_variant, splice_region_variant Exon 4 of 14 1 NM_015630.4 ENSP00000258484.6 Q52LR7
EPC2ENST00000397424.2 linkc.247C>T p.Leu83Phe missense_variant, splice_region_variant Exon 4 of 5 3 ENSP00000380569.2 C9J1X4
EPC2ENST00000457184.5 linkc.388C>T p.Leu130Phe missense_variant, splice_region_variant Exon 5 of 5 5 ENSP00000415543.2 E7ETK1
EPC2ENST00000491099.1 linkn.33C>T non_coding_transcript_exon_variant Exon 1 of 2 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 21, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.460C>T (p.L154F) alteration is located in exon 4 (coding exon 4) of the EPC2 gene. This alteration results from a C to T substitution at nucleotide position 460, causing the leucine (L) at amino acid position 154 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
.;T;.
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.39
T;T;T
MetaSVM
Benign
-0.37
T
MutationAssessor
Benign
1.8
.;L;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-1.9
N;N;N
REVEL
Benign
0.16
Sift
Benign
0.041
D;T;D
Sift4G
Benign
0.094
T;T;T
Polyphen
1.0
.;D;.
Vest4
0.54
MutPred
0.39
.;Gain of loop (P = 0.0013);.;
MVP
0.28
MPC
0.46
ClinPred
0.87
D
GERP RS
5.9
Varity_R
0.25
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-149511496; API