chr6-145627253-A-C

Variant names:

• chr6-145627253-A-C
• rs7753694
• NM_005670.4:c.*163T>G

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.*163T>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 0.0128 in 1,529,212 control chromosomes in the GnomAD database, including 2,061 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.067 (1138 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (923 hom.)
• Consequence: EPM2A NM_005670.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.970
• 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: 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 6-145627253-A-C is Benign according to our data. Variant chr6-145627253-A-C is described in ClinVar as Benign. ClinVar VariationId is 1290853.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 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.*163T>G		3_prime_UTR	Exon 4 of 4	NP_005661.1	O95278-1
	EPM2A	NM_001360057.2		c.*242T>G		3_prime_UTR	Exon 3 of 3	NP_001346986.1	O95278-5
	EPM2A	NM_001360064.2		c.*163T>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.*163T>G		3_prime_UTR	Exon 4 of 4	ENSP00000356489.3	O95278-1
	EPM2A	ENST00000638262.1	TSL:1	c.*242T>G		3_prime_UTR	Exon 3 of 3	ENSP00000492876.1	O95278-5
	EPM2A	ENST00000639423.1	TSL:1	c.*163T>G		3_prime_UTR	Exon 4 of 4	ENSP00000492701.1	O95278-8

Frequencies

GnomAD3 genomes AF: 0.0666 AC: 10136 AN: 152162 Hom.: 1134 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.0616

GnomAD4 exome AF: 0.00685 AC: 9436 AN: 1376932 Hom.: 923 Cov.: 32 AF XY: 0.00597 AC XY: 4058 AN XY: 679224

African (AFR) AF: 0.236 AC: 7266 AN: 30792

American (AMR) AF: 0.0174 AC: 569 AN: 32646

Ashkenazi Jewish (ASJ) AF: 0.00121 AC: 26 AN: 21492

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39146

South Asian (SAS) AF: 0.000465 AC: 34 AN: 73164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36100

Middle Eastern (MID) AF: 0.0102 AC: 40 AN: 3928

European-Non Finnish (NFE) AF: 0.000570 AC: 617 AN: 1082538

Other (OTH) AF: 0.0155 AC: 883 AN: 57126

GnomAD4 genome AF: 0.0666 AC: 10146 AN: 152280 Hom.: 1138 Cov.: 33 AF XY: 0.0645 AC XY: 4805 AN XY: 74482

African (AFR) AF: 0.226 AC: 9366 AN: 41524

American (AMR) AF: 0.0365 AC: 558 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68020

Other (OTH) AF: 0.0610 AC: 129 AN: 2116

Alfa AF: 0.0268 Hom.: 1058

Bravo AF: 0.0783

Asia WGS AF: 0.00837 AC: 30 AN: 3478

ClinVar

ClinVar submissions

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	-0.75
CADD	Benign	7.8
DANN	Benign	0.90
PhyloP100		0.97
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: rs7753694; hg19: chr6-145948389;