17-12992957-C-T

Variant names:

• chr17-12992957-C-T
• rs119484086
• NM_018127.7:c.2342G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PS3 PP5 BP4 BS1_Supporting

The NM_018127.7(ELAC2):​c.2342G>A​(p.Arg781His) variant causes a missense change. The variant allele was found at a frequency of 0.0009 in 1,611,198 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000616709: Published functional studies are contradictory: some suggesting impaired mitochondrial enzymatic activity of ELAC2, and others suggesting mitochondrial enzymatic activity similar to wildtype (PMID:31045291, 15863270, 16636667)". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R781L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (1 hom.)
• Consequence: ELAC2 NM_018127.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:4
• Conservation: PhyloP100: 5.52
• Publications: 25 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 3 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000616709: Published functional studies are contradictory: some suggesting impaired mitochondrial enzymatic activity of ELAC2, and others suggesting mitochondrial enzymatic activity similar to wildtype (PMID: 31045291, 15863270, 16636667)
• PP5: Variant 17-12992957-C-T is Pathogenic according to our data. Variant chr17-12992957-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5058.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2580968). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000538 (82/152314) while in subpopulation NFE AF = 0.000955 (65/68032). AF 95% confidence interval is 0.000768. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2342G>A	p.Arg781His	missense	Exon 24 of 24	NP_060597.4
	ELAC2	NM_173717.2		c.2339G>A	p.Arg780His	missense	Exon 24 of 24	NP_776065.1
	ELAC2	NM_001165962.2		c.2222G>A	p.Arg741His	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.2342G>A	p.Arg781His	missense	Exon 24 of 24	ENSP00000337445.4	Q9BQ52-1
	ELAC2	ENST00000923774.1		c.2444G>A	p.Arg815His	missense	Exon 25 of 25	ENSP00000593833.1
	ELAC2	ENST00000860253.1		c.2366G>A	p.Arg789His	missense	Exon 25 of 25	ENSP00000530312.1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000530 AC: 132 AN: 249148 AF XY: 0.000437

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000152

Gnomad NFE exome AF: 0.000968

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000938 AC: 1368 AN: 1458884 Hom.: 1 Cov.: 32 AF XY: 0.000908 AC XY: 659 AN XY: 725942

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.000201 AC: 9 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.000139 AC: 7 AN: 50460

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

European-Non Finnish (NFE) AF: 0.00117 AC: 1303 AN: 1111990

Other (OTH) AF: 0.000663 AC: 40 AN: 60374

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74474

African (AFR) AF: 0.000217 AC: 9 AN: 41564

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000955 AC: 65 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000842 Hom.: 0

Bravo AF: 0.000453

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.00109

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	2	-	Combined oxidative phosphorylation defect type 17 (5)
3	1	-	not provided (4)
-	1	-	Inborn genetic diseases (1)
1	-	-	Prostate cancer, hereditary, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.096	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.87
MPC		0.83
ClinPred		0.15	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.59
Mutation Taster		=37/63	disease causing (ClinVar)

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: rs119484086; hg19: chr17-12896274; COSMIC: COSV52394689; COSMIC: COSV52394689;