3-36992693-G-A

Position:

• chr3-36992693-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014805.4(EPM2AIP1):​c.385C>T​(p.Leu129=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,613,910 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (110 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (101 hom.)
• Consequence: EPM2AIP1 NM_014805.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.30

Genes affected

EPM2AIP1 (HGNC:19735): (EPM2A interacting protein 1) The EPM2A gene, which encodes laforin, is mutated in an autosomal recessive form of adolescent progressive myoclonus epilepsy. The protein encoded by this gene binds to laforin, but its function is not known. This gene is intronless. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-36992693-G-A is Benign according to our data. Variant chr3-36992693-G-A is described in ClinVar as [Benign]. Clinvar id is 787011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPM2AIP1	NM_014805.4	c.385C>T	p.Leu129=	synonymous_variant	1/1	ENST00000322716.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPM2AIP1	ENST00000322716.8	c.385C>T	p.Leu129=	synonymous_variant	1/1		NM_014805.4	P1
EPM2AIP1	ENST00000623924.1	c.63+185C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3182 AN: 152140 Hom.: 107 Cov.: 33

Gnomad AFR AF: 0.0730

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00519 AC: 1292 AN: 249112 Hom.: 51 AF XY: 0.00397 AC XY: 536 AN XY: 135134

Gnomad AFR exome AF: 0.0755

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00208 AC: 3036 AN: 1461652 Hom.: 101 Cov.: 34 AF XY: 0.00181 AC XY: 1314 AN XY: 727110

Gnomad4 AFR exome AF: 0.0755

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000755

Gnomad4 OTH exome AF: 0.00419

GnomAD4 genome AF: 0.0210 AC: 3193 AN: 152258 Hom.: 110 Cov.: 33 AF XY: 0.0201 AC XY: 1496 AN XY: 74450

Gnomad4 AFR AF: 0.0731

Gnomad4 AMR AF: 0.00778

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0112 Hom.: 18

Bravo AF: 0.0241

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.0
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4647203; hg19: chr3-37034184;