Genetic Variant ELAC2:p.Arg28Ser (chr17-13017866-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018127.7(ELAC2):c.82C>A(p.Arg28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,402,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R28H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ELAC2
NM_018127.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.48

Publications

0 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:

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ACMG classification

Classification was made for transcript

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=0.2521787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELAC2	NM_018127.7 link	c.82C>A	p.Arg28Ser	missense_variant	Exon 1 of 24	ENST00000338034.9	NP_060597.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELAC2	ENST00000338034.9 link	c.82C>A	p.Arg28Ser	missense_variant	Exon 1 of 24	1	NM_018127.7	ENSP00000337445.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000114

AC:

AN:

1402268

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

692804

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32024

American (AMR)

AF:

0.00

AC:

AN:

36770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24916

East Asian (EAS)

AF:

0.00

AC:

AN:

36532

South Asian (SAS)

AF:

0.00

AC:

AN:

80504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4880

European-Non Finnish (NFE)

AF:

0.0000138

AC:

AN:

1083964

Other (OTH)

AF:

0.0000172

AC:

AN:

58084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

T;.;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

2.0

M;.;M;.

PhyloP100

2.5

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.31

N;N;N;.

REVEL

Benign

0.18

Sift

Uncertain

0.019

D;D;D;.

Sift4G

Benign

0.39

T;D;T;T

Polyphen

0.87

P;P;.;.

Vest4

0.20

MutPred

0.24

Gain of phosphorylation at R28 (P = 0.0033);Gain of phosphorylation at R28 (P = 0.0033);Gain of phosphorylation at R28 (P = 0.0033);Gain of phosphorylation at R28 (P = 0.0033);

MVP

0.76

MPC

0.30

ClinPred

0.85

GERP RS

4.2

PromoterAI

-0.033

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.16

gMVP

0.54

Mutation Taster

=91/9

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over