22-17181552-C-G

Position:

• chr22-17181552-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001282225.2(ADA2):​c.1467G>C​(p.Glu489Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000917 in 1,612,710 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (1 hom.)
• Consequence: ADA2 NM_001282225.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.394

Genes affected

ADA2 (HGNC:1839): (adenosine deaminase 2) This gene encodes a member of a subfamily of the adenosine deaminase protein family. The encoded protein is one of two adenosine deaminases found in humans, which regulate levels of the signaling molecule, adenosine. The encoded protein is secreted from monocytes undergoing differentiation and may regulate cell proliferation and differentiation. This gene may be responsible for some of the phenotypic features associated with cat eye syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10696912).
• BP6: Variant 22-17181552-C-G is Benign according to our data. Variant chr22-17181552-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 569098.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADA2	NM_001282225.2	c.1467G>C	p.Glu489Asp	missense_variant	10/10	ENST00000399837.8	NP_001269154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADA2	ENST00000399837.8	c.1467G>C	p.Glu489Asp	missense_variant	10/10	1	NM_001282225.2	ENSP00000382731	P1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000955

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000398 AC: 100 AN: 251338 Hom.: 0 AF XY: 0.000397 AC XY: 54 AN XY: 135850

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000774

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000960 AC: 1402 AN: 1460508 Hom.: 1 Cov.: 29 AF XY: 0.000921 AC XY: 669 AN XY: 726644

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74360

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000955

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000650 Hom.: 0

Bravo AF: 0.000487

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 11, 2022

DNA sequence analysis of the ADA2 gene demonstrated a sequence change, c.1467G>C, in exon 10 that results in an amino acid change, p.Glu489Asp. This sequence change does not appear to have been previously described in individuals with ADA2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.075% in the European subpopulation (dbSNP rs61738625). The p.Glu489Asp change affects a poorly conserved amino acid residue located in a domain of the ADA2 protein that is known to be functional. The p.Glu489Asp substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu489Asp change remains unknown at this time. -

Vasculitis due to ADA2 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 489 of the ADA2 protein (p.Glu489Asp). This variant is present in population databases (rs61738625, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with ADA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 569098). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 22, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

ADA2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	2.9
DANN	Benign	0.94
DEOGEN2	Benign	0.047	T;T;T;.;T;T;.;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.39	T;.;.;T;.;T;.;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.3	.;N;N;N;N;.;N;.
REVEL	Benign	0.15
Sift	Benign	0.14	.;T;T;T;T;.;T;.
Sift4G	Benign	0.085	T;T;T;D;T;.;T;.
Polyphen		0.0020, 0.024	.;B;B;B;B;B;.;.
Vest4		0.036
MutPred		0.60		.;Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);.;Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);.;.;
MVP		0.62
MPC		0.049
ClinPred		0.015	T
GERP RS		1.3
Varity_R		0.19
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61738625; hg19: chr22-17662442;