2-148645072-A-G

Variant names:

• chr2-148645072-A-G
• rs1273140092
• NM_015630.4:c.55A>G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_015630.4(EPC2):​c.55A>G​(p.Ile19Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000154 in 1,431,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: EPC2 NM_015630.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.42

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14718834).
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPC2	NM_015630.4	c.55A>G	p.Ile19Val	missense_variant	Exon 1 of 14	ENST00000258484.11	NP_056445.3
EPC2	XM_011510941.3	c.55A>G	p.Ile19Val	missense_variant	Exon 1 of 14		XP_011509243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPC2	ENST00000258484.11	c.55A>G	p.Ile19Val	missense_variant	Exon 1 of 14	1	NM_015630.4	ENSP00000258484.6
EPC2	ENST00000457184	c.-18A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 5	5		ENSP00000415543.2
EPC2	ENST00000409654.5	c.55A>G	p.Ile19Val	missense_variant	Exon 1 of 3	3		ENSP00000387097.1
EPC2	ENST00000457184	c.-18A>G		5_prime_UTR_variant	Exon 2 of 5	5		ENSP00000415543.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000986 AC: 2 AN: 202830 Hom.: 0 AF XY: 0.00000915 AC XY: 1 AN XY: 109242

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 SAS exome AF: 0.0000384

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000154 AC: 22 AN: 1431980 Hom.: 0 Cov.: 34 AF XY: 0.0000141 AC XY: 10 AN XY: 709446

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.0000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000137

Gnomad4 OTH exome AF: 0.0000507

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.55A>G (p.I19V) alteration is located in exon 1 (coding exon 1) of the EPC2 gene. This alteration results from a A to G substitution at nucleotide position 55, causing the isoleucine (I) at amino acid position 19 to be replaced by a valine (V). 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	0.072
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.034
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.075	N;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.15	N;N
REVEL	Benign	0.098
Sift	Benign	1.0	T;T
Sift4G	Benign	0.84	T;T
Polyphen		0.047	B;.
Vest4		0.20
MutPred		0.57		Loss of catalytic residue at I19 (P = 0.0494);Loss of catalytic residue at I19 (P = 0.0494);
MVP		0.36
MPC		1.6
ClinPred		0.11	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs1273140092; hg19: chr2-149402641;