17-12996585-C-T

Variant names:

• chr17-12996585-C-T
• rs5030739
• NM_018127.7:c.1621G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018127.7(ELAC2):​c.1621G>A​(p.Ala541Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0371 in 1,614,038 control chromosomes in the GnomAD database, including 1,293 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (97 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1196 hom.)
• Consequence: ELAC2 NM_018127.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 3.67
• Publications: 66 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009242713).
• BP6: Variant 17-12996585-C-T is Benign according to our data. Variant chr17-12996585-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 5056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0293 (4465/152274) while in subpopulation SAS AF = 0.0429 (207/4828). AF 95% confidence interval is 0.0385. There are 97 homozygotes in GnomAd4. There are 2183 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 97 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELAC2	NM_018127.7	MANE Select	c.1621G>A	p.Ala541Thr	missense	Exon 17 of 24	NP_060597.4
	ELAC2	NM_173717.2		c.1618G>A	p.Ala540Thr	missense	Exon 17 of 24	NP_776065.1
	ELAC2	NM_001165962.2		c.1501G>A	p.Ala501Thr	missense	Exon 16 of 23	NP_001159434.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELAC2	ENST00000338034.9	TSL:1 MANE Select	c.1621G>A	p.Ala541Thr	missense	Exon 17 of 24	ENSP00000337445.4
	ELAC2	ENST00000395962.6	TSL:2	c.1564G>A	p.Ala522Thr	missense	Exon 17 of 24	ENSP00000379291.1
	ELAC2	ENST00000426905.7	TSL:2	c.1501G>A	p.Ala501Thr	missense	Exon 16 of 23	ENSP00000405223.3

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4467 AN: 152156 Hom.: 97 Cov.: 33

Gnomad AFR AF: 0.00603

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0422

Gnomad FIN AF: 0.0437

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0347 AC: 8725 AN: 251120 AF XY: 0.0358

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.0301

Gnomad ASJ exome AF: 0.0506

Gnomad EAS exome AF: 0.00669

Gnomad FIN exome AF: 0.0439

Gnomad NFE exome AF: 0.0390

Gnomad OTH exome AF: 0.0408

GnomAD4 exome AF: 0.0379 AC: 55441 AN: 1461764 Hom.: 1196 Cov.: 31 AF XY: 0.0383 AC XY: 27818 AN XY: 727196

African (AFR) AF: 0.00588 AC: 197 AN: 33480

American (AMR) AF: 0.0293 AC: 1309 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0560 AC: 1463 AN: 26136

East Asian (EAS) AF: 0.00398 AC: 158 AN: 39700

South Asian (SAS) AF: 0.0451 AC: 3888 AN: 86258

European-Finnish (FIN) AF: 0.0462 AC: 2461 AN: 53300

Middle Eastern (MID) AF: 0.0537 AC: 310 AN: 5768

European-Non Finnish (NFE) AF: 0.0391 AC: 43440 AN: 1112002

Other (OTH) AF: 0.0367 AC: 2215 AN: 60396

GnomAD4 genome AF: 0.0293 AC: 4465 AN: 152274 Hom.: 97 Cov.: 33 AF XY: 0.0293 AC XY: 2183 AN XY: 74454

African (AFR) AF: 0.00601 AC: 250 AN: 41568

American (AMR) AF: 0.0308 AC: 471 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 204 AN: 3468

East Asian (EAS) AF: 0.00560 AC: 29 AN: 5176

South Asian (SAS) AF: 0.0429 AC: 207 AN: 4828

European-Finnish (FIN) AF: 0.0437 AC: 464 AN: 10610

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0397 AC: 2701 AN: 68020

Other (OTH) AF: 0.0336 AC: 71 AN: 2112

Alfa AF: 0.0361 Hom.: 348

Bravo AF: 0.0275

TwinsUK AF: 0.0434 AC: 161

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.0391 AC: 336

ExAC AF: 0.0343 AC: 4159

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.0389

EpiControl AF: 0.0385

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Combined oxidative phosphorylation defect type 17 (3)
-	-	2	not provided (2)
1	-	-	Prostate cancer, hereditary, 2 (1)
-	-	1	Prostate cancer, hereditary, 2;C3809526:Combined oxidative phosphorylation defect type 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.81
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.081
Eigen_PC	Benign	0.0043
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Benign	0.20	T
Sift4G	Benign	0.16	T
Polyphen		0.34	B
Vest4		0.29
MPC		0.23
ClinPred		0.043	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.55
Mutation Taster		=100/0	polymorphism (auto)

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: rs5030739; hg19: chr17-12899902; COSMIC: COSV61648260; COSMIC: COSV61648260;