18-36138270-C-CT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_018255.4(ELP2):c.293dup(p.Leu98PhefsTer10) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

ELP2
NM_018255.4 frameshift, splice_region

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 2.84

Variant links:

Genes affected

ELP2 (HGNC:18248): (elongator acetyltransferase complex subunit 2) The protein encoded by this gene is a core subunit of the elongator complex, a histone acetyltransferase complex that associates with RNA polymerase II. In addition to histone acetylation, the encoded protein effects transcriptional elongation and may help remodel chromatin. [provided by RefSeq, May 2016]

ELP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 18-36138270-C-CT is Pathogenic according to our data. Variant chr18-36138270-C-CT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1012186.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP2	NM_018255.4 linkuse as main transcript	c.293dup	p.Leu98PhefsTer10	frameshift_variant, splice_region_variant	4/22	ENST00000358232.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP2	ENST00000358232.11 linkuse as main transcript	c.293dup	p.Leu98PhefsTer10	frameshift_variant, splice_region_variant	4/22	1	NM_018255.4	P1	Q6IA86-1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251392

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.0000289

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:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000335

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000629

Hom.:

Bravo

AF:

0.000314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 58

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jun 29, 2023	PVS1, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 10, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 24, 2023	The ELP2 c.293dup (p.Leu98PhefsTer10) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in trans with a missense variant in two individuals with an intellectual developmental disorder (PMID: 33976153). The highest frequency of the p.Leu98PhefsTer10 variant in the Genome Aggregation Database is 0.001183 in the African/African American population (version 3.1.2). Based on the available evidence, the c.293dup (p.Leu98PhefsTer10) variant is classified as likely pathogenic for intellectual developmental disorder. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2024	The p.Leu98PhefsX10 variant in ELP2 has been reported in 1 individual with syndromic intellectual disability and segregated with disease in 1 affected individuals from 1 family (Kojic 2021 PMID: 33976153). This variant has been identified in 0.12% (49/41418) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This variant has also been reported in ClinVar (Variation ID 1012186). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 98 and leads to a premature termination codon 10 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Other loss of function variants have been reported in at least 6 individuals with autosomal recessive intellectual developmental disorder (Kojic 2021 PMID: 33976153, Russo PMID: 34653680, Lunke 2020 PMID: 32573669); however the role of loss of function in the disease mechanism is still uncertain. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PP1. -

Intellectual disability, profound

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Wainwright Lab, University Of Queensland

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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