17-12992865-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018127.7(ELAC2):c.2434C>T(p.Arg812Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,461,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R812Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: ELAC2 NM_018127.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.184

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19669199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELAC2	NM_018127.7	c.2434C>T	p.Arg812Trp	missense_variant	24/24	ENST00000338034.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELAC2	ENST00000338034.9	c.2434C>T	p.Arg812Trp	missense_variant	24/24	1	NM_018127.7	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250766 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461142 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 726932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000949

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.2434C>T (p.R812W) alteration is located in exon 24 (coding exon 24) of the ELAC2 gene. This alteration results from a C to T substitution at nucleotide position 2434, causing the arginine (R) at amino acid position 812 to be replaced by a tryptophan (W). 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

Invitae

Sep 10, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 812 of the ELAC2 protein (p.Arg812Trp). This variant is present in population databases (rs767611235, gnomAD 0.006%). 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: 1504125). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 21, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.047	T;.;.
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.76	T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.14
MutPred		0.30		Loss of MoRF binding (P = 0.0709);.;.;
MVP		0.80
MPC		0.63
ClinPred		0.72	D
GERP RS		3.3
Varity_R		0.12
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs767611235; hg19: chr17-12896182; COSMIC: COSV52397735; COSMIC: COSV52397735;