17-12992877-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.2422C>T(p.Pro808Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. P808L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ELAC2 NM_018127.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

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=0.08237603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELAC2	NM_018127.7	c.2422C>T	p.Pro808Ser	missense_variant	24/24	ENST00000338034.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELAC2	ENST00000338034.9	c.2422C>T	p.Pro808Ser	missense_variant	24/24	1	NM_018127.7	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined oxidative phosphorylation defect type 17 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 08, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 808 of the ELAC2 protein (p.Pro808Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ELAC2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	13
Dann	Benign	0.90
DEOGEN2	Benign	0.017	T;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.082	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	0.71	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.85	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.097	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.013	B;B;.
Vest4		0.047
MutPred		0.097		Gain of phosphorylation at P808 (P = 0.0343);.;.;
MVP		0.69
MPC		0.19
ClinPred		0.20	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.041
gMVP		0.34

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: rs2040253504; hg19: chr17-12896194;