6-145625777-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005670.4(EPM2A):​c.*1639C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000845 in 1,182,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: EPM2A NM_005670.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.814
• 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.45e-7 AC: 1 AN: 1182916 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 599560

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27826

American (AMR) AF: 0.00 AC: 0 AN: 41818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24208

East Asian (EAS) AF: 0.00 AC: 0 AN: 37870

South Asian (SAS) AF: 0.00 AC: 0 AN: 77588

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5288

European-Non Finnish (NFE) AF: 0.00000116 AC: 1 AN: 865000

Other (OTH) AF: 0.00 AC: 0 AN: 51074

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.47
DANN	Benign	0.62
PhyloP100		-0.81

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;