NM_005670.4:c.*172A>G

Variant names:

• chr6-145627244-T-C
• rs375400866
• NM_005670.4:c.*172A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005670.4(EPM2A):​c.*172A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,510,360 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: EPM2A NM_005670.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.927
• Publications: 0 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: ClinGen, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 6-145627244-T-C is Benign according to our data. Variant chr6-145627244-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1216701.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00226 (344/152342) while in subpopulation NFE AF = 0.00228 (155/68016). AF 95% confidence interval is 0.00199. There are 1 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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.*172A>G		3_prime_UTR	Exon 4 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001360057.2		c.*251A>G		3_prime_UTR	Exon 3 of 3	NP_001346986.1	O95278-5
	EPM2A	NM_001360064.2		c.*172A>G		3_prime_UTR	Exon 4 of 4	NP_001346993.1	O95278-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2A	ENST00000367519.9	TSL:1 MANE Select	c.*172A>G		3_prime_UTR	Exon 4 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000638262.1	TSL:1	c.*251A>G		3_prime_UTR	Exon 3 of 3	ENSP00000492876.1	O95278-5
	EPM2A	ENST00000639423.1	TSL:1	c.*172A>G		3_prime_UTR	Exon 4 of 4	ENSP00000492701.1	O95278-8

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152224 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00163

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00187 AC: 2538 AN: 1358018 Hom.: 6 Cov.: 32 AF XY: 0.00184 AC XY: 1230 AN XY: 667762

African (AFR) AF: 0.000231 AC: 7 AN: 30302

American (AMR) AF: 0.000342 AC: 10 AN: 29212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20644

East Asian (EAS) AF: 0.00 AC: 0 AN: 38770

South Asian (SAS) AF: 0.000142 AC: 10 AN: 70440

European-Finnish (FIN) AF: 0.00794 AC: 279 AN: 35118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3790

European-Non Finnish (NFE) AF: 0.00199 AC: 2132 AN: 1073316

Other (OTH) AF: 0.00177 AC: 100 AN: 56426

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152342 Hom.: 1 Cov.: 33 AF XY: 0.00258 AC XY: 192 AN XY: 74502

African (AFR) AF: 0.000529 AC: 22 AN: 41586

American (AMR) AF: 0.00163 AC: 25 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00228 AC: 155 AN: 68016

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00139

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.0
DANN	Benign	0.72
PhyloP100		-0.93
Mutation Taster		=100/0	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: rs375400866; hg19: chr6-145948380;