Genetic Variant NM_018127.7:c.1621G>C (chr17-12996585-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018127.7(ELAC2):c.1621G>C(p.Ala541Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. A541T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

ELAC2
NM_018127.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.67

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

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.1621G>C	p.Ala541Pro	missense	Exon 17 of 24	NP_060597.4
ELAC2	NM_173717.2		c.1618G>C	p.Ala540Pro	missense	Exon 17 of 24	NP_776065.1
ELAC2	NM_001165962.2		c.1501G>C	p.Ala501Pro	missense	Exon 16 of 23	NP_001159434.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ELAC2	ENST00000338034.9	TSL:1 MANE Select	c.1621G>C	p.Ala541Pro	missense	Exon 17 of 24	ENSP00000337445.4
ELAC2	ENST00000923774.1		c.1723G>C	p.Ala575Pro	missense	Exon 18 of 25	ENSP00000593833.1
ELAC2	ENST00000860253.1		c.1645G>C	p.Ala549Pro	missense	Exon 18 of 25	ENSP00000530312.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.2

PhyloP100

3.7

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.65

Sift

Uncertain

0.012

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.94

MutPred

0.56

Loss of stability (P = 0.086)

MVP

0.93

MPC

0.80

ClinPred

0.97

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.91

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over