Genetic Variant ELAC2:p.Ser52Cys (chr17-13017793-G-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018127.7(ELAC2):c.155C>G(p.Ser52Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,607,972 control chromosomes in the GnomAD database, including 5 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S52F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 5 hom. )

Consequence

ELAC2
NM_018127.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01075846).

BP6

Variant 17-13017793-G-C is Benign according to our data. Variant chr17-13017793-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241271.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000584 (89/152362) while in subpopulation EAS AF = 0.00328 (17/5180). AF 95% confidence interval is 0.00209. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 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>G	p.Ser52Cys	missense	Exon 1 of 24	NP_060597.4
ELAC2	NM_173717.2		c.155C>G	p.Ser52Cys	missense	Exon 1 of 24	NP_776065.1
ELAC2	NM_001165962.2		c.155C>G	p.Ser52Cys	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>G	p.Ser52Cys	missense	Exon 1 of 24	ENSP00000337445.4
ELAC2	ENST00000395962.6	TSL:2	c.155C>G	p.Ser52Cys	missense	Exon 1 of 24	ENSP00000379291.1
ELAC2	ENST00000426905.7	TSL:2	c.155C>G	p.Ser52Cys	missense	Exon 1 of 23	ENSP00000405223.3

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00327

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000433

AC:

AN:

223824

AF XY:

0.000470

show subpopulations

Gnomad AFR exome

AF:

0.000991

Gnomad AMR exome

AF:

0.000483

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00241

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000165

Gnomad OTH exome

AF:

0.00110

GnomAD4 exome

AF:

0.000319

AC:

464

AN:

1455610

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

216

AN XY:

723740

show subpopulations

African (AFR)

AF:

0.000539

AC:

AN:

33406

American (AMR)

AF:

0.000454

AC:

AN:

44068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25952

East Asian (EAS)

AF:

0.00137

AC:

AN:

39488

South Asian (SAS)

AF:

0.000222

AC:

AN:

85534

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51420

Middle Eastern (MID)

AF:

0.000524

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.000198

AC:

220

AN:

1109958

Other (OTH)

AF:

0.00216

AC:

130

AN:

60064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

123

154

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:

0.000584

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41588

American (AMR)

AF:

0.000327

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00328

AC:

AN:

5180

South Asian (SAS)

AF:

0.000414

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:

0.000250

AC:

AN:

68034

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.0000182

Hom.:

Bravo

AF:

0.000635

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.000300

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Feb 10, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 24, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Prostate cancer, hereditary, 2;C3809526:Combined oxidative phosphorylation defect type 17

Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ELAC2 NM_018127.6 exon 1 p.Ser52Cys (c.155C>G): This variant has not been reported in the literature but is present in 0.2% (51/18600) of East Asian alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/17-12921110-G-C). This variant is present in ClinVar (Variation ID:241271). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain

Inborn genetic diseases

Benign:1

Dec 13, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

ELAC2-related disorder

Benign:1

Apr 15, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

Jan 30, 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

0.075

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.021

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.55

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.90

PhyloP100

0.21

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.97

REVEL

Benign

0.13

Sift

Benign

0.043

Sift4G

Uncertain

0.053

Polyphen

0.90

Vest4

0.12

MVP

0.74

MPC

0.34

ClinPred

0.015

GERP RS

3.1

PromoterAI

0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.057

gMVP

0.31

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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