18-36136313-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_018255.4(ELP2):c.224C>G(p.Ser75Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000369 in 1,610,290 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ELP2 NM_018255.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.15

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007561952).
• BP6: Variant 18-36136313-C-G is Benign according to our data. Variant chr18-36136313-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 710518.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00197 (300/152274) while in subpopulation AFR AF= 0.00686 (285/41552). AF 95% confidence interval is 0.0062. There are 1 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP2	NM_018255.4	c.224C>G	p.Ser75Cys	missense_variant	3/22	ENST00000358232.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP2	ENST00000358232.11	c.224C>G	p.Ser75Cys	missense_variant	3/22	1	NM_018255.4	P1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 299 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000502 AC: 126 AN: 251180 Hom.: 0 AF XY: 0.000331 AC XY: 45 AN XY: 135794

Gnomad AFR exome AF: 0.00735

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: 0.000327

GnomAD4 exome AF: 0.000202 AC: 294 AN: 1458016 Hom.: 0 Cov.: 28 AF XY: 0.000135 AC XY: 98 AN XY: 725650

Gnomad4 AFR exome AF: 0.00728

Gnomad4 AMR exome AF: 0.000268

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: 0.00000271

Gnomad4 OTH exome AF: 0.000548

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74462

Gnomad4 AFR AF: 0.00686

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.00220

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000675 AC: 82

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30755224) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

ELP2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Benign	0.85
DEOGEN2	Benign	0.027	T;.;.;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.79	T;T;T;T;T;T
MetaRNN	Benign	0.0076	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.4	M;M;M;M;M;M
MutationTaster	Benign	0.98	N;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.4	N;D;D;D;N;N
REVEL	Benign	0.084
Sift	Benign	0.14	T;T;T;T;T;T
Sift4G	Uncertain	0.029	D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D
Vest4		0.29
MVP		0.65
MPC		0.094
ClinPred		0.075	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.38

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

LitVar

Other links and lift over

dbSNP: rs74438152; hg19: chr18-33716276;