Genetic Variant ELAC2:p.Ser52Phe (chr17-13017793-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018127.7(ELAC2):c.155C>T(p.Ser52Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,607,976 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S52C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 3 hom. )

Consequence

ELAC2
NM_018127.7 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:5

Conservation

PhyloP100: 0.207

Publications

3 publications found

Variant links:

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

ELAC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.005798787).

BP6

Variant 17-13017793-G-A is Benign according to our data. Variant chr17-13017793-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 241272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00213 (324/152366) while in subpopulation AFR AF = 0.0068 (283/41588). AF 95% confidence interval is 0.00615. There are 1 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ELAC2	NM_018127.7	MANE Select	c.155C>T	p.Ser52Phe	missense	Exon 1 of 24	NP_060597.4
ELAC2	NM_173717.2		c.155C>T	p.Ser52Phe	missense	Exon 1 of 24	NP_776065.1
ELAC2	NM_001165962.2		c.155C>T	p.Ser52Phe	missense	Exon 1 of 23	NP_001159434.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ELAC2	ENST00000338034.9	TSL:1 MANE Select	c.155C>T	p.Ser52Phe	missense	Exon 1 of 24	ENSP00000337445.4
ELAC2	ENST00000395962.6	TSL:2	c.155C>T	p.Ser52Phe	missense	Exon 1 of 24	ENSP00000379291.1
ELAC2	ENST00000426905.7	TSL:2	c.155C>T	p.Ser52Phe	missense	Exon 1 of 23	ENSP00000405223.3

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

323

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00680

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000715

AC:

160

AN:

223824

AF XY:

0.000599

show subpopulations

Gnomad AFR exome

AF:

0.00717

Gnomad AMR exome

AF:

0.000302

Gnomad ASJ exome

AF:

0.00255

Gnomad EAS exome

AF:

0.000469

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000366

GnomAD4 exome

AF:

0.000376

AC:

548

AN:

1455610

Hom.:

Cov.:

AF XY:

0.000327

AC XY:

237

AN XY:

723740

show subpopulations

African (AFR)

AF:

0.00769

AC:

257

AN:

33406

American (AMR)

AF:

0.000386

AC:

AN:

44068

Ashkenazi Jewish (ASJ)

AF:

0.00243

AC:

AN:

25952

East Asian (EAS)

AF:

0.000355

AC:

AN:

39488

South Asian (SAS)

AF:

0.000210

AC:

AN:

85534

European-Finnish (FIN)

AF:

0.0000583

AC:

AN:

51420

Middle Eastern (MID)

AF:

0.000524

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.000114

AC:

127

AN:

1109958

Other (OTH)

AF:

0.000766

AC:

AN:

60064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00213

AC:

324

AN:

152366

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00680

AC:

283

AN:

41588

American (AMR)

AF:

0.000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.000772

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000784

Hom.:

Bravo

AF:

0.00254

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00370

AC:

ESP6500EA

AF:

0.000352

AC:

ExAC

AF:

0.000691

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 15, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 29, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Prostate cancer, hereditary, 2

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ELAC2-related disorder

Benign:1

Sep 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Combined oxidative phosphorylation defect type 17

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.022

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.27

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.90

PhyloP100

0.21

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.2

REVEL

Benign

0.057

Sift

Benign

0.047

Sift4G

Uncertain

0.054

Polyphen

0.29

Vest4

0.085

MVP

0.75

MPC

0.20

ClinPred

0.0044

GERP RS

3.1

PromoterAI

0.037

Neutral

(source)

Varity_R

0.040

gMVP

0.27

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over