18-36138378-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018255.4(ELP2):c.397G>A(p.Ala133Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ELP2 NM_018255.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP2	NM_018255.4	c.397G>A	p.Ala133Thr	missense_variant	4/22	ENST00000358232.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP2	ENST00000358232.11	c.397G>A	p.Ala133Thr	missense_variant	4/22	1	NM_018255.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461820 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2023

The c.397G>A (p.A133T) alteration is located in exon 4 (coding exon 4) of the ELP2 gene. This alteration results from a G to A substitution at nucleotide position 397, causing the alanine (A) at amino acid position 133 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0099	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.026	T;.;.;.;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D;T;D;T;T;T
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.5	M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D;D;T;T;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		1.0	D;P;.;.;.;P
Vest4		0.55
MutPred		0.63		Gain of catalytic residue at A133 (P = 0.1185);Gain of catalytic residue at A133 (P = 0.1185);Gain of catalytic residue at A133 (P = 0.1185);Gain of catalytic residue at A133 (P = 0.1185);Gain of catalytic residue at A133 (P = 0.1185);Gain of catalytic residue at A133 (P = 0.1185);
MVP		0.64
MPC		0.25
ClinPred		0.96	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.54

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: rs1671838145; hg19: chr18-33718341;