rs1555571246

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4BP6BS1BS2

The NM_018127.7(ELAC2):c.2353_2415dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT(p.Asp805_Gly806insArgGluLeuArgGlnValArgAlaAlaLeuLeuSerArgGluLeuAlaGlyGlyLeuGluAsp) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,456,472 control chromosomes in the GnomAD database, including 27 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 27 hom. )

Failed GnomAD Quality Control

Consequence

ELAC2
NM_018127.7 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -0.695

Publications

0 publications found

Variant links:

Genes affected

ELAC2 (HGNC:14198): (elaC ribonuclease Z 2) The protein encoded by this gene has a C-terminal domain with tRNA 3′ processing endoribonuclease activity, which catalyzes the removal of the 3' trailer from precursor tRNAs. The protein also interacts with activated Smad family member 2 (Smad2) and its nuclear partner forkhead box H1 (also known as FAST-1), and reduced expression can suppress transforming growth factor-beta induced growth arrest. Mutations in this gene result in an increased risk of prostate cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ELAC2 Gene-Disease associations (from GenCC):

combined oxidative phosphorylation defect type 17
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ELAC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_018127.7.

BP6

Variant 17-12992883-C-CATCCTCCAGGCCGCCTGCCAGCTCCCTGGACAGGAGGGCCGCCCGCACCTGCCGCAGCTCCCG is Benign according to our data. Variant chr17-12992883-C-CATCCTCCAGGCCGCCTGCCAGCTCCCTGGACAGGAGGGCCGCCCGCACCTGCCGCAGCTCCCG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408865.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00162 (2353/1456472) while in subpopulation NFE AF = 0.00181 (2003/1108126). AF 95% confidence interval is 0.00174. There are 27 homozygotes in GnomAdExome4. There are 1184 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELAC2	NM_018127.7 link	c.2353_2415dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT	p.Asp805_Gly806insArgGluLeuArgGlnValArgAlaAlaLeuLeuSerArgGluLeuAlaGlyGlyLeuGluAsp	conservative_inframe_insertion	Exon 24 of 24	ENST00000338034.9	NP_060597.4	Q9BQ52-1A0A0S2Z5M8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELAC2	ENST00000338034.9 link	c.2353_2415dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT	p.Asp805_Gly806insArgGluLeuArgGlnValArgAlaAlaLeuLeuSerArgGluLeuAlaGlyGlyLeuGluAsp	conservative_inframe_insertion	Exon 24 of 24	1	NM_018127.7	ENSP00000337445.4		Q9BQ52-1

Frequencies

GnomAD3 genomes

AF:

0.00170

AC:

259

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00350

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000744

AC:

186

AN:

249920

AF XY:

0.000813

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00141

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00162

AC:

2353

AN:

1456472

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

1184

AN XY:

724764

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33464

American (AMR)

AF:

0.000671

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00334

AC:

174

AN:

52082

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00181

AC:

2003

AN:

1108126

Other (OTH)

AF:

0.00201

AC:

121

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

162

244

325

406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00170

AC:

259

AN:

152178

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41546

American (AMR)

AF:

0.000784

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00350

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00281

AC:

191

AN:

67988

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00211

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jun 04, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In-frame insertion of 21 amino acids in a non-repeat region -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ELAC2: BS2 -

Inborn genetic diseases

Uncertain:1

Jan 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2353_2415dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT (p.R785_D805dup) gross duplication spans coding exons XXXX through XXXX in the ELAC2 gene; however, the exact breakpoints of the deletion were not determined. Gene duplications are expected to disrupt gene function; however, it is unclear whether this duplication is disruptive to the ELAC2 gene, or is merely duplicated adjacent to the original xxxx gene or located elsewhere in the genome (Mazzarella, R and Schlessinger, D Genome Res 1998;8:1007-1021). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Combined oxidative phosphorylation defect type 17

Uncertain:1

Oct 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.2353_2415dup, results in the insertion of 21 amino acid(s) of the ELAC2 protein (p.Arg785_Asp805dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with ELAC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408865). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

ELAC2-related disorder

Benign:1

Jun 17, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

PhyloP100

-0.69

Mutation Taster

=86/14

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over