chr17-15945352-C-T

Variant names:

• chr17-15945352-C-T
• rs61755963
• NM_000676.4:c.104C>T

Variant summary

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

The NM_000676.4(ADORA2B):​c.104C>T​(p.Ala35Val) variant causes a missense change. The variant allele was found at a frequency of 0.00115 in 1,608,930 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A35G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (12 hom.)
• Consequence: ADORA2B NM_000676.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.53
• Publications: 0 publications found

Genes affected

ADORA2B (HGNC:264): (adenosine A2b receptor) This gene encodes an adenosine receptor that is a member of the G protein-coupled receptor superfamily. This integral membrane protein stimulates adenylate cyclase activity in the presence of adenosine. This protein also interacts with netrin-1, which is involved in axon elongation. The gene is located near the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046432614).
• BP6: Variant 17-15945352-C-T is Benign according to our data. Variant chr17-15945352-C-T is described in ClinVar as Benign. ClinVar VariationId is 785557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0061 (930/152358) while in subpopulation AFR AF = 0.0212 (880/41582). AF 95% confidence interval is 0.02. There are 7 homozygotes in GnomAd4. There are 454 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000676.4. 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
	ADORA2B	NM_000676.4	MANE Select	c.104C>T	p.Ala35Val	missense	Exon 1 of 2	NP_000667.1	P29275

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADORA2B	ENST00000304222.3	TSL:1 MANE Select	c.104C>T	p.Ala35Val	missense	Exon 1 of 2	ENSP00000304501.2	P29275

Frequencies

GnomAD3 genomes AF: 0.00610 AC: 929 AN: 152240 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00248

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00151 AC: 366 AN: 243004 AF XY: 0.00116

Gnomad AFR exome AF: 0.0206

Gnomad AMR exome AF: 0.000965

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000818

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000632 AC: 920 AN: 1456572 Hom.: 12 Cov.: 31 AF XY: 0.000519 AC XY: 376 AN XY: 724656

African (AFR) AF: 0.0228 AC: 761 AN: 33428

American (AMR) AF: 0.000965 AC: 43 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49970

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111124

Other (OTH) AF: 0.00116 AC: 70 AN: 60260

GnomAD4 genome AF: 0.00610 AC: 930 AN: 152358 Hom.: 7 Cov.: 33 AF XY: 0.00609 AC XY: 454 AN XY: 74504

African (AFR) AF: 0.0212 AC: 880 AN: 41582

American (AMR) AF: 0.00248 AC: 38 AN: 15312

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00131 Hom.: 4

Bravo AF: 0.00737

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.83	N
PhyloP100		5.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.011	B
Vest4		0.085
MVP		0.50
MPC		0.15
ClinPred		0.043	T
GERP RS		3.6
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.20
gMVP		0.26
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs61755963; hg19: chr17-15848666;