chr6-145625777-G-A

Variant names:

• chr6-145625777-G-A
• rs73568389
• NM_005670.4:c.*1639C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005670.4(EPM2A):​c.*1639C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,335,036 control chromosomes in the GnomAD database, including 2,151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.069 (1234 hom., cov: 33)
  • Exomes 𝑓: 0.0077 (917 hom.)
• Consequence: EPM2A NM_005670.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.814
• Publications: 2 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-145625777-G-A is Benign according to our data. Variant chr6-145625777-G-A is described in ClinVar as Benign. ClinVar VariationId is 1227152.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

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.*1639C>T		3_prime_UTR	Exon 4 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001360057.2		c.*1718C>T		3_prime_UTR	Exon 3 of 3	NP_001346986.1	O95278-5
	EPM2A	NM_001360064.2		c.*1639C>T		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.*1639C>T		3_prime_UTR	Exon 4 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000638262.1	TSL:1	c.*1718C>T		3_prime_UTR	Exon 3 of 3	ENSP00000492876.1	O95278-5
	EPM2A	ENST00000639423.1	TSL:1	c.*1639C>T		3_prime_UTR	Exon 4 of 4	ENSP00000492701.1	O95278-8

Frequencies

GnomAD3 genomes AF: 0.0691 AC: 10503 AN: 152022 Hom.: 1230 Cov.: 33

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.0637

GnomAD4 exome AF: 0.00770 AC: 9111 AN: 1182894 Hom.: 917 Cov.: 16 AF XY: 0.00656 AC XY: 3932 AN XY: 599544

African (AFR) AF: 0.246 AC: 6833 AN: 27804

American (AMR) AF: 0.0165 AC: 690 AN: 41818

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 30 AN: 24208

East Asian (EAS) AF: 0.0000528 AC: 2 AN: 37870

South Asian (SAS) AF: 0.000516 AC: 40 AN: 77586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52244

Middle Eastern (MID) AF: 0.0129 AC: 68 AN: 5288

European-Non Finnish (NFE) AF: 0.000618 AC: 535 AN: 865004

Other (OTH) AF: 0.0179 AC: 913 AN: 51072

GnomAD4 genome AF: 0.0691 AC: 10514 AN: 152142 Hom.: 1234 Cov.: 33 AF XY: 0.0671 AC XY: 4989 AN XY: 74380

African (AFR) AF: 0.234 AC: 9715 AN: 41468

American (AMR) AF: 0.0372 AC: 569 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68004

Other (OTH) AF: 0.0630 AC: 133 AN: 2110

Alfa AF: 0.0315 Hom.: 174

Bravo AF: 0.0811

Asia WGS AF: 0.00982 AC: 35 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.87
CADD	Benign	2.1
DANN	Benign	0.68
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

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: rs73568389; hg19: chr6-145946913;