rs1555571246

Positions:

chr17-12992883-C-CATCCTCCAGGCCGCCTGCCAGCTCCCTGGACAGGAGGGCCGCCCGCACCTGCCGCAGCTCCCG

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4BS1_SupportingBS2

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. 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

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 links:

ELAC2 (HGNC:):

ELAC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_018127.7.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 1184 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELAC2	NM_018127.7 linkuse as main transcript	c.2353_2415dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT	p.Asp805_Gly806insArgGluLeuArgGlnValArgAlaAlaLeuLeuSerArgGluLeuAlaGlyGlyLeuGluAsp	conservative_inframe_insertion	24/24	ENST00000338034.9	NP_060597.4	Q9BQ52-1A0A0S2Z5M8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELAC2	ENST00000338034.9 linkuse as main transcript	c.2353_2415dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT	p.Asp805_Gly806insArgGluLeuArgGlnValArgAlaAlaLeuLeuSerArgGluLeuAlaGlyGlyLeuGluAsp	conservative_inframe_insertion	24/24	1	NM_018127.7	ENSP00000337445.4		Q9BQ52-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

259

AN:

152060

Hom.:

Cov.:

FAILED QC

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

GnomAD3 exomes

AF:

0.000744

AC:

186

AN:

249920

Hom.:

AF XY:

0.000813

AC XY:

110

AN XY:

135222

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 SAS exome

AF:

0.0000653

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

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00334

Gnomad4 NFE exome

AF:

0.00181

Gnomad4 OTH exome

AF:

0.00201

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

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00350

Gnomad4 NFE

AF:

0.00281

Gnomad4 OTH

AF:

0.00284

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

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2024	Has not been previously published as pathogenic or benign to our knowledge; In-frame insertion of 21 amino acids in a non-repeat region -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ELAC2: PM4, BS2 -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 20, 2022

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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2022

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

Splicing

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