chr17-13011784-T-C

Position:

chr17-13011784-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 6P and 9B. PVS1_ModeratePP3_StrongBP6BS1BS2

The NM_018127.7(ELAC2):c.560-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,614,178 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0026 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

ELAC2
NM_018127.7 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.04

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.047964532 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.3, offset of -31, new splice context is: tgtcagctcaccttgtgcAGtgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 17-13011784-T-C is Benign according to our data. Variant chr17-13011784-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235643.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00257 (391/152290) while in subpopulation AFR AF= 0.00876 (364/41560). AF 95% confidence interval is 0.00802. There are 3 homozygotes in gnomad4. There are 187 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELAC2	NM_018127.7 linkuse as main transcript	c.560-2A>G		splice_acceptor_variant		ENST00000338034.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELAC2	ENST00000338034.9 linkuse as main transcript	c.560-2A>G		splice_acceptor_variant		1	NM_018127.7	P2	Q9BQ52-1

Frequencies

GnomAD3 genomes

AF:

0.00258

AC:

392

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00881

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000696

AC:

175

AN:

251456

Hom.:

AF XY:

0.000552

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0103

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000249

AC:

364

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

148

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00962

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.00257

AC:

391

AN:

152290

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

187

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00876

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000422

Hom.:

Bravo

AF:

0.00286

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000832

AC:

101

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2020	This variant is associated with the following publications: (PMID: 26046366) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ELAC2: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2016	- -

Combined oxidative phosphorylation defect type 17

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Benign

0.96

Eigen

Pathogenic

0.82

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

D;D;D

GERP RS

4.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.69

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.69

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over