dbSNP rs2125688966: EPM2AIP1:p.Ala436Val (chr3-36991771-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014805.4(EPM2AIP1):c.1307C>T(p.Ala436Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EPM2AIP1
NM_014805.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.95

Publications

0 publications found

Variant links:

Genes affected

EPM2AIP1 (HGNC:19735): (EPM2A interacting protein 1) The EPM2A gene, which encodes laforin, is mutated in an autosomal recessive form of adolescent progressive myoclonus epilepsy. The protein encoded by this gene binds to laforin, but its function is not known. This gene is intronless. [provided by RefSeq, Oct 2008]

EPM2AIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.19898748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPM2AIP1	NM_014805.4 link	c.1307C>T	p.Ala436Val	missense_variant	Exon 1 of 1	ENST00000322716.8	NP_055620.1	Q7L775

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPM2AIP1	ENST00000322716.8 link	c.1307C>T	p.Ala436Val	missense_variant	Exon 1 of 1	6	NM_014805.4	ENSP00000406027.1	Q7L775
EPM2AIP1	ENST00000624586.1 link	c.387+110C>T		intron_variant	Intron 1 of 1	5		ENSP00000485091.1	A0A096LNL1
EPM2AIP1	ENST00000623924.1 link	c.62+1107C>T		intron_variant	Intron 1 of 2	5		ENSP00000485489.1	A0A096LPB0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461294

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726928

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33426

American (AMR)

AF:

0.00

AC:

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111758

Other (OTH)

AF:

0.00

AC:

AN:

60356

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1307C>T (p.A436V) alteration is located in exon 1 (coding exon 1) of the EPM2AIP1 gene. This alteration results from a C to T substitution at nucleotide position 1307, causing the alanine (A) at amino acid position 436 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

0.18

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.68

M_CAP

Benign

0.0085

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

4.9

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.75

REVEL

Benign

0.11

Sift

Benign

0.23

Sift4G

Uncertain

0.024

Polyphen

0.59

Vest4

0.31

MutPred

0.28

Loss of helix (P = 0.1706);

MVP

0.32

MPC

0.91

ClinPred

0.73

GERP RS

4.8

PromoterAI

0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.22

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over