18-36138270-C-CT

Variant names:

• chr18-36138270-C-CT
• rs529659464
• NM_018255.4:c.293dupT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PVS1 PP5 BS1_Supporting

The NM_018255.4(ELP2):​c.293dupT​(p.Leu98PhefsTer10) variant causes a frameshift 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. 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 2.84
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 58

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 VariationId is 1012186.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000335 (51/152250) while in subpopulation AFR AF = 0.00118 (49/41540). AF 95% confidence interval is 0.000916. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018255.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP2	NM_018255.4	MANE Select	c.293dupT	p.Leu98PhefsTer10	frameshift	Exon 4 of 22	NP_060725.1	Q6IA86-1
	ELP2	NM_001242875.3		c.293dupT	p.Leu98PhefsTer10	frameshift	Exon 4 of 23	NP_001229804.1	Q6IA86-6
	ELP2	NM_001324466.2		c.293dupT	p.Leu98PhefsTer10	frameshift	Exon 4 of 22	NP_001311395.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP2	ENST00000358232.11	TSL:1 MANE Select	c.293dupT	p.Leu98PhefsTer10	frameshift	Exon 4 of 22	ENSP00000350967.6	Q6IA86-1
	ELP2	ENST00000423854.6	TSL:1	c.293dupT	p.Leu98PhefsTer10	frameshift	Exon 4 of 19	ENSP00000391202.2	Q6IA86-7
	ELP2	ENST00000542824.5	TSL:1	c.293dupT	p.Leu98PhefsTer10	frameshift	Exon 4 of 20	ENSP00000443800.1	Q6IA86-2

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152132 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251392 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461720 Hom.: 0 Cov.: 34 AF XY: 0.0000261 AC XY: 19 AN XY: 727170

African (AFR) AF: 0.00122 AC: 41 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111920

Other (OTH) AF: 0.000215 AC: 13 AN: 60388

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74438

African (AFR) AF: 0.00118 AC: 49 AN: 41540

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000629 Hom.: 0

Bravo AF: 0.000314

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Intellectual disability, autosomal recessive 58 (3)
-	2	-	not provided (2)
1	-	-	Profound intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=16/184	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs529659464; hg19: chr18-33718233;