17-12992877-G-A

Variant names:

• chr17-12992877-G-A
• rs2040253504
• NM_018127.7:c.2422C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. 17/22 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
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08237603).

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.2422C>T	p.Pro808Ser	missense	Exon 24 of 24	NP_060597.4
	ELAC2	NM_173717.2		c.2419C>T	p.Pro807Ser	missense	Exon 24 of 24	NP_776065.1
	ELAC2	NM_001165962.2		c.2302C>T	p.Pro768Ser	missense	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.2422C>T	p.Pro808Ser	missense	Exon 24 of 24	ENSP00000337445.4	Q9BQ52-1
	ELAC2	ENST00000923774.1		c.2524C>T	p.Pro842Ser	missense	Exon 25 of 25	ENSP00000593833.1
	ELAC2	ENST00000860253.1		c.2446C>T	p.Pro816Ser	missense	Exon 25 of 25	ENSP00000530312.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Combined oxidative phosphorylation defect type 17 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.10
Sift	Benign	0.097	T
Sift4G	Benign	0.24	T
Polyphen		0.013	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

Other links and lift over

dbSNP: rs2040253504; hg19: chr17-12896194;