NM_018127.7:c.2375C>A

Variant names:

• chr17-12992924-G-T
• rs767378629
• NM_018127.7:c.2375C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018127.7(ELAC2):​c.2375C>A​(p.Ala792Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A792V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ELAC2 NM_018127.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.72
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05397868).

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.2375C>A	p.Ala792Glu	missense	Exon 24 of 24	NP_060597.4
	ELAC2	NM_173717.2		c.2372C>A	p.Ala791Glu	missense	Exon 24 of 24	NP_776065.1
	ELAC2	NM_001165962.2		c.2255C>A	p.Ala752Glu	missense	Exon 23 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.2375C>A	p.Ala792Glu	missense	Exon 24 of 24	ENSP00000337445.4
	ELAC2	ENST00000395962.6	TSL:2	c.2318C>A	p.Ala773Glu	missense	Exon 24 of 24	ENSP00000379291.1
	ELAC2	ENST00000426905.7	TSL:2	c.2255C>A	p.Ala752Glu	missense	Exon 23 of 23	ENSP00000405223.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458750 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725906

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.2
DANN	Benign	0.89
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.91	L
PhyloP100		1.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.066
Sift	Benign	0.075	T
Sift4G	Benign	0.93	T
Polyphen		0.0070	B
Vest4		0.083
MutPred		0.23		Loss of MoRF binding (P = 0.0518)
MVP		0.57
MPC		0.22
ClinPred		0.076	T
GERP RS		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.44

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: rs767378629; hg19: chr17-12896241;