2-148753927-C-T

Variant names:

• chr2-148753927-C-T
• NM_015630.4:c.460C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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: Splicing: ADA: 0.9965
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

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]

ACMG classification

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
EPC2	NM_015630.4	c.460C>T	p.Leu154Phe	missense_variant, splice_region_variant	Exon 4 of 14	ENST00000258484.11	NP_056445.3
EPC2	XM_011510941.3	c.460C>T	p.Leu154Phe	missense_variant, splice_region_variant	Exon 4 of 14		XP_011509243.1
EPC2	XM_011510943.4	c.193C>T	p.Leu65Phe	missense_variant, splice_region_variant	Exon 3 of 13		XP_011509245.1
EPC2	XM_047443897.1	c.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
EPC2	ENST00000258484.11	c.460C>T	p.Leu154Phe	missense_variant, splice_region_variant	Exon 4 of 14	1	NM_015630.4	ENSP00000258484.6
EPC2	ENST00000397424.2	c.247C>T	p.Leu83Phe	missense_variant, splice_region_variant	Exon 4 of 5	3		ENSP00000380569.2
EPC2	ENST00000457184.5	c.388C>T	p.Leu130Phe	missense_variant, splice_region_variant	Exon 5 of 5	5		ENSP00000415543.2
EPC2	ENST00000491099.1	n.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

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;