rs1555571246

Variant names:

• chr17-12992883-C-CATCCTCCAGGCCGCCTGCCAGCTCCCTGGACAGGAGGGCCGCCCGCACCTGCCGCAGCTCCCG
• rs1555571246
• NM_018127.7:c.2353_2415dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3 O:1
• Conservation: PhyloP100: -0.695
• Publications: 0 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018127.7. 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
	ELAC2	NM_018127.7	MANE Select	c.2353_2415dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT	p.Asp805_Gly806insArgGluLeuArgGlnValArgAlaAlaLeuLeuSerArgGluLeuAlaGlyGlyLeuGluAsp	conservative_inframe_insertion	Exon 24 of 24	NP_060597.4
	ELAC2	NM_173717.2		c.2350_2412dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT	p.Asp804_Gly805insArgGluLeuArgGlnValArgAlaAlaLeuLeuSerArgGluLeuAlaGlyGlyLeuGluAsp	conservative_inframe_insertion	Exon 24 of 24	NP_776065.1
	ELAC2	NM_001165962.2		c.2233_2295dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT	p.Asp765_Gly766insArgGluLeuArgGlnValArgAlaAlaLeuLeuSerArgGluLeuAlaGlyGlyLeuGluAsp	conservative_inframe_insertion	Exon 23 of 23	NP_001159434.1	Q9BQ52-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELAC2	ENST00000338034.9	TSL:1 MANE Select	c.2353_2415dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT	p.Asp805_Gly806insArgGluLeuArgGlnValArgAlaAlaLeuLeuSerArgGluLeuAlaGlyGlyLeuGluAsp	conservative_inframe_insertion	Exon 24 of 24	ENSP00000337445.4	Q9BQ52-1
	ELAC2	ENST00000923774.1		c.2455_2517dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT	p.Asp839_Gly840insArgGluLeuArgGlnValArgAlaAlaLeuLeuSerArgGluLeuAlaGlyGlyLeuGluAsp	conservative_inframe_insertion	Exon 25 of 25	ENSP00000593833.1
	ELAC2	ENST00000860253.1		c.2377_2439dupCGGGAGCTGCGGCAGGTGCGGGCGGCCCTCCTGTCCAGGGAGCTGGCAGGCGGCCTGGAGGAT	p.Asp813_Gly814insArgGluLeuArgGlnValArgAlaAlaLeuLeuSerArgGluLeuAlaGlyGlyLeuGluAsp	conservative_inframe_insertion	Exon 25 of 25	ENSP00000530312.1

Frequencies

GnomAD3 genomes AF: 0.00170 AC: 259 AN: 152060 Hom.: 0 Cov.: 33

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

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.: 27 Cov.: 32 AF XY: 0.00163 AC XY: 1184 AN XY: 724764

African (AFR) AF: 0.000329 AC: 11 AN: 33464

American (AMR) AF: 0.000671 AC: 30 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.00334 AC: 174 AN: 52082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00181 AC: 2003 AN: 1108126

Other (OTH) AF: 0.00201 AC: 121 AN: 60242

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00170 AC: 259 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.00177 AC XY: 132 AN XY: 74388

African (AFR) AF: 0.000313 AC: 13 AN: 41546

American (AMR) AF: 0.000784 AC: 12 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00350 AC: 37 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 67988

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00211 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	Combined oxidative phosphorylation defect type 17 (2)
-	-	1	ELAC2-related disorder (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.69
Mutation Taster		=86/14	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1555571246; hg19: chr17-12896200;