rs146597836

Variant names:

• chr22-17189987-C-T
• rs146597836
• NM_001282225.2:c.927G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001282225.2(ADA2):​c.927G>A​(p.Met309Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,614,082 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M309T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: ADA2 NM_001282225.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:8
• Conservation: PhyloP100: 1.07
• Publications: 9 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, Orphanet, Labcorp Genetics (formerly Invitae)
• Sneddon syndrome

  Inheritance: AD, AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• polyarteritis nodosa

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• Diamond-Blackfan anemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004589975).
• BP6: Variant 22-17189987-C-T is Benign according to our data. Variant chr22-17189987-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 375247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00154 (2255/1461760) while in subpopulation MID AF = 0.012 (69/5766). AF 95% confidence interval is 0.0097. There are 4 homozygotes in GnomAdExome4. There are 1196 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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.927G>A	p.Met309Ile	missense	Exon 6 of 10	NP_001269154.1	Q9NZK5-1
	ADA2	NM_001282226.2		c.927G>A	p.Met309Ile	missense	Exon 6 of 10	NP_001269155.1	Q9NZK5-1
	ADA2	NM_001282227.2		c.801G>A	p.Met267Ile	missense	Exon 6 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.927G>A	p.Met309Ile	missense	Exon 6 of 10	ENSP00000382731.2	Q9NZK5-1
	ADA2	ENST00000262607.3	TSL:1	c.927G>A	p.Met309Ile	missense	Exon 5 of 9	ENSP00000262607.2	Q9NZK5-1
	ADA2	ENST00000885359.1		c.1044G>A	p.Met348Ile	missense	Exon 7 of 11	ENSP00000555418.1

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00175 AC: 441 AN: 251468 AF XY: 0.00185

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00154 AC: 2255 AN: 1461760 Hom.: 4 Cov.: 30 AF XY: 0.00164 AC XY: 1196 AN XY: 727200

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.00161 AC: 72 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00517 AC: 135 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00215 AC: 185 AN: 86244

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53412

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5766

European-Non Finnish (NFE) AF: 0.00148 AC: 1648 AN: 1111918

Other (OTH) AF: 0.00224 AC: 135 AN: 60388

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00152 AC XY: 113 AN XY: 74480

African (AFR) AF: 0.000241 AC: 10 AN: 41572

American (AMR) AF: 0.00131 AC: 20 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00188 AC: 128 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00173

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00198 AC: 240

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	not specified (2)
-	-	1	ADA2-related disorder (1)
-	-	1	Autoinflammatory syndrome (1)
1	-	-	Behcet disease (1)
-	-	1	Vasculitis due to ADA2 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	9.5
DANN	Benign	0.70
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.55	T
PhyloP100		1.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.29
Sift	Benign	0.43	T
Sift4G	Benign	0.59	T
Polyphen		0.0020	B
Vest4		0.29
MutPred		0.71		Loss of MoRF binding (P = 0.1393)
MVP		0.71
MPC		0.048
ClinPred		0.0025	T
GERP RS		2.9
Varity_R		0.26
gMVP		0.53
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs146597836; hg19: chr22-17670877; COSMIC: COSV106090421; COSMIC: COSV106090421;