chr3-36991787-G-C

Variant names:

• chr3-36991787-G-C
• rs2125689002
• NM_014805.4:c.1291C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014805.4(EPM2AIP1):​c.1291C>G​(p.Leu431Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,098 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: 0.0000021 (0 hom.)
• Consequence: EPM2AIP1 NM_014805.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.175
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30159378).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014805.4. 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
	EPM2AIP1	NM_014805.4	MANE Select	c.1291C>G	p.Leu431Val	missense	Exon 1 of 1	NP_055620.1	Q7L775

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2AIP1	ENST00000322716.8	TSL:6 MANE Select	c.1291C>G	p.Leu431Val	missense	Exon 1 of 1	ENSP00000406027.1	Q7L775
	EPM2AIP1	ENST00000624586.1	TSL:5	c.387+94C>G		intron	N/A	ENSP00000485091.1	A0A096LNL1
	EPM2AIP1	ENST00000623924.1	TSL:5	c.62+1091C>G		intron	N/A	ENSP00000485489.1	A0A096LPB0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461098 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726878

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111716

Other (OTH) AF: 0.00 AC: 0 AN: 60334

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.17
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.16
Sift	Benign	0.056	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.68		Gain of helix (P = 0.062)
MVP		0.22
MPC		1.5
ClinPred		0.71	D
GERP RS		3.9
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.24
Mutation Taster		=90/10	polymorphism

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: rs2125689002; hg19: chr3-37033278;