Variant 18-50920573-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002396.5(ME2):c.844+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,574,270 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.010 ( 36 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 27 hom. )

Consequence

ME2
NM_002396.5 splice_region, intron

Scores

Splicing: ADA: 0.00001362

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.50

Variant links:

Genes affected

ME2 (HGNC:6984): (malic enzyme 2) This gene encodes a mitochondrial NAD-dependent malic enzyme, a homotetrameric protein, that catalyzes the oxidative decarboxylation of malate to pyruvate. It had previously been weakly linked to a syndrome known as Friedreich ataxia that has since been shown to be the result of mutation in a completely different gene. Certain single-nucleotide polymorphism haplotypes of this gene have been shown to increase the risk for idiopathic generalized epilepsy. Alternatively spliced transcript variants encoding different isoforms found for this gene. [provided by RefSeq, Dec 2009]

ME2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 18-50920573-A-C is Benign according to our data. Variant chr18-50920573-A-C is described in ClinVar as [Benign]. Clinvar id is 3033318.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1543/152304) while in subpopulation AFR AF= 0.0346 (1438/41562). AF 95% confidence interval is 0.0331. There are 36 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
ME2	NM_002396.5 linkuse as main transcript	c.844+8A>C	splice_region_variant, intron_variant	ENST00000321341.11
ME2	NM_001168335.2 linkuse as main transcript	c.844+8A>C	splice_region_variant, intron_variant
ME2	NR_174094.1 linkuse as main transcript	n.1047+8A>C	splice_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ME2	ENST00000321341.11 linkuse as main transcript	c.844+8A>C		splice_region_variant, intron_variant		1	NM_002396.5	P1	P23368-1

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1543

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0347

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00280

AC:

605

AN:

216008

Hom.:

AF XY:

0.00192

AC XY:

226

AN XY:

117992

show subpopulations

Gnomad AFR exome

AF:

0.0373

Gnomad AMR exome

AF:

0.00152

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000289

Gnomad OTH exome

AF:

0.00139

GnomAD4 exome

AF:

0.000967

AC:

1375

AN:

1421966

Hom.:

Cov.:

AF XY:

0.000828

AC XY:

586

AN XY:

707334

show subpopulations

Gnomad4 AFR exome

AF:

0.0389

Gnomad4 AMR exome

AF:

0.00158

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000250

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000100

Gnomad4 OTH exome

AF:

0.00167

GnomAD4 genome

AF:

0.0101

AC:

1543

AN:

152304

Hom.:

Cov.:

AF XY:

0.00980

AC XY:

730

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0346

Gnomad4 AMR

AF:

0.00575

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00530

Hom.:

Bravo

AF:

0.0117

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ME2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

6.3

DANN

Benign

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.012

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over