rs144565191

Variant names:

• chr6-145635319-T-A
• rs144565191
• NM_005670.4:c.644A>T

Your query was ambiguous. Multiple possible variants found:

• chr6-145635319-T-A
• chr6-145635319-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005670.4(EPM2A):​c.644A>T​(p.Asp215Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: EPM2A NM_005670.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.67
• Publications: 1 publications found

Genes affected

EPM2A (HGNC:3413): (EPM2A glucan phosphatase, laforin) This gene encodes a dual-specificity phosphatase and may be involved in the regulation of glycogen metabolism. The protein acts on complex carbohydrates to prevent glycogen hyperphosphorylation, thus avoiding the formation of insoluble aggregates. Loss-of-function mutations in this gene have been associated with Lafora disease, a rare, adult-onset recessive neurodegenerative disease, which results in myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by the accumulation of insoluble particles called Lafora bodies, which are derived from glycogen. [provided by RefSeq, Jan 2018]

EPM2A Gene-Disease associations (from GenCC):

• Lafora disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2504207).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005670.4. 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
	EPM2A	NM_005670.4	MANE Select	c.644A>T	p.Asp215Val	missense	Exon 3 of 4	NP_005661.1
	EPM2A	NM_001018041.2		c.644A>T	p.Asp215Val	missense	Exon 3 of 5	NP_001018051.1
	EPM2A	NM_001368130.1		c.644A>T	p.Asp215Val	missense	Exon 3 of 3	NP_001355059.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.644A>T	p.Asp215Val	missense	Exon 3 of 4	ENSP00000356489.3
	EPM2A	ENST00000435470.2	TSL:1	c.644A>T	p.Asp215Val	missense	Exon 3 of 5	ENSP00000405913.2
	EPM2A	ENST00000639423.1	TSL:1	c.230A>T	p.Asp77Val	missense	Exon 3 of 4	ENSP00000492701.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251452 AF XY: 0.000184

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000220 AC: 322 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.000238 AC XY: 173 AN XY: 727238

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000270 AC: 300 AN: 1111974

Other (OTH) AF: 0.000166 AC: 10 AN: 60396

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74480

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.0000907

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000327

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	-	Myoclonic epilepsy of Lafora 1 (1)
-	1	-	Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	0.00093	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.015	D
Sift4G	Benign	0.071	T
Polyphen		0.58	P
Vest4		0.50
MVP		0.99
MPC		0.68
ClinPred		0.18	T
GERP RS		5.9
gMVP		0.61
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs144565191; hg19: chr6-145956455;