rs61738625

Variant names:

• chr22-17181552-C-G
• rs61738625
• NM_001282225.2:c.1467G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-17181552-C-G
• chr22-17181552-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E489Q) has been classified as Uncertain significance.

• 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:2
• Conservation: PhyloP100: 0.394
• Publications: 2 publications found

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]

ADA2 Gene-Disease associations (from GenCC):

• deficiency of adenosine deaminase 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• vasculitis due to ADA2 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• polyarteritis nodosa

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• Sneddon syndrome

  Inheritance: AR, AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• 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 VariationId is 569098.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282225.2. 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
	ADA2	NM_001282225.2	MANE Select	c.1467G>C	p.Glu489Asp	missense	Exon 10 of 10	NP_001269154.1	Q9NZK5-1
	ADA2	NM_001282226.2		c.1467G>C	p.Glu489Asp	missense	Exon 10 of 10	NP_001269155.1	Q9NZK5-1
	ADA2	NM_001282227.2		c.1341G>C	p.Glu447Asp	missense	Exon 10 of 10	NP_001269156.1	B4E3Q4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADA2	ENST00000399837.8	TSL:1 MANE Select	c.1467G>C	p.Glu489Asp	missense	Exon 10 of 10	ENSP00000382731.2	Q9NZK5-1
	ADA2	ENST00000262607.3	TSL:1	c.1467G>C	p.Glu489Asp	missense	Exon 9 of 9	ENSP00000262607.2	Q9NZK5-1
	ADA2	ENST00000885359.1		c.1584G>C	p.Glu528Asp	missense	Exon 11 of 11	ENSP00000555418.1

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

GnomAD2 exomes AF: 0.000398 AC: 100 AN: 251338 AF XY: 0.000397

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 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

African (AFR) AF: 0.0000598 AC: 2 AN: 33444

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86216

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53414

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5586

European-Non Finnish (NFE) AF: 0.00122 AC: 1357 AN: 1110972

Other (OTH) AF: 0.000530 AC: 32 AN: 60328

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

African (AFR) AF: 0.000217 AC: 9 AN: 41454

American (AMR) AF: 0.000196 AC: 3 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000955 AC: 65 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2088

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Autoinflammatory syndrome (1)
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	1	Sneddon syndrome;C3887654:Vasculitis due to ADA2 deficiency (1)
-	1	-	Vasculitis due to ADA2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.65	T
PhyloP100		0.39
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Benign	0.14	T
Sift4G	Benign	0.085	T
Polyphen		0.0020	B
Vest4		0.036
MutPred		0.60		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
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs61738625; hg19: chr22-17662442;