chr22-17207277-G-C

Variant names:

• chr22-17207277-G-C
• rs587777241
• NM_001282225.2:c.336C>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_001282225.2(ADA2):​c.336C>G​(p.His112Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000351 in 1,453,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H112Y) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: ADA2 NM_001282225.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.127
• Publications: 10 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001282225.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-17207279-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1472946.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 22-17207277-G-C is Pathogenic according to our data. Variant chr22-17207277-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 120302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.336C>G	p.His112Gln	missense	Exon 3 of 10	NP_001269154.1	Q9NZK5-1
	ADA2	NM_001282226.2		c.336C>G	p.His112Gln	missense	Exon 3 of 10	NP_001269155.1	Q9NZK5-1
	ADA2	NM_001282227.2		c.210C>G	p.His70Gln	missense	Exon 3 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.336C>G	p.His112Gln	missense	Exon 3 of 10	ENSP00000382731.2	Q9NZK5-1
	ADA2	ENST00000262607.3	TSL:1	c.336C>G	p.His112Gln	missense	Exon 2 of 9	ENSP00000262607.2	Q9NZK5-1
	ADA2	ENST00000885359.1		c.336C>G	p.His112Gln	missense	Exon 3 of 11	ENSP00000555418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250956 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000351 AC: 51 AN: 1453262 Hom.: 0 Cov.: 31 AF XY: 0.0000374 AC XY: 27 AN XY: 721038

African (AFR) AF: 0.00 AC: 0 AN: 33344

American (AMR) AF: 0.0000224 AC: 1 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5270

European-Non Finnish (NFE) AF: 0.0000434 AC: 48 AN: 1105158

Other (OTH) AF: 0.0000334 AC: 2 AN: 59932

GnomAD4 genome Cov.: 32

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Vasculitis due to ADA2 deficiency (3)
2	-	-	not provided (2)
1	-	-	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		0.13
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.88		Gain of sheet (P = 0.0149)
MVP		0.96
MPC		0.31
ClinPred		0.98	D
GERP RS		0.29
Varity_R		0.98
gMVP		0.91
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587777241; hg19: chr22-17688167;