16-3983435-T-C

Variant names:

• chr16-3983435-T-C
• rs2230739
• NM_001116.4:c.2316A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001116.4(ADCY9):​c.2316A>G​(p.Ile772Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,598,584 control chromosomes in the GnomAD database, including 71,122 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (5539 hom., cov: 33)
  • Exomes 𝑓: 0.30 (65583 hom.)
• Consequence: ADCY9 NM_001116.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 72 publications found

Genes affected

ADCY9 (HGNC:240): (adenylate cyclase 9) Adenylate cyclase is a membrane bound enzyme that catalyses the formation of cyclic AMP from ATP. It is regulated by a family of G protein-coupled receptors, protein kinases, and calcium. The type 9 adenylyl cyclase is a widely distributed adenylyl cyclase, and it is stimulated by beta-adrenergic receptor activation but is insensitive to forskolin, calcium, and somatostatin. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2301078E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001116.4. 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
	ADCY9	NM_001116.4	MANE Select	c.2316A>G	p.Ile772Met	missense	Exon 7 of 11	NP_001107.2	O60503

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY9	ENST00000294016.8	TSL:1 MANE Select	c.2316A>G	p.Ile772Met	missense	Exon 7 of 11	ENSP00000294016.3	O60503
	ADCY9	ENST00000936467.1		c.2406A>G	p.Ile802Met	missense	Exon 8 of 12	ENSP00000606526.1
	ADCY9	ENST00000868252.1		c.2316A>G	p.Ile772Met	missense	Exon 6 of 10	ENSP00000538311.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39130 AN: 151924 Hom.: 5547 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.267

GnomAD2 exomes AF: 0.288 AC: 64859 AN: 225288 AF XY: 0.292

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.424

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.298 AC: 431682 AN: 1446542 Hom.: 65583 Cov.: 33 AF XY: 0.299 AC XY: 214905 AN XY: 718194

African (AFR) AF: 0.130 AC: 4328 AN: 33196

American (AMR) AF: 0.231 AC: 9802 AN: 42478

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 8102 AN: 25880

East Asian (EAS) AF: 0.388 AC: 15195 AN: 39124

South Asian (SAS) AF: 0.277 AC: 23273 AN: 84086

European-Finnish (FIN) AF: 0.286 AC: 14984 AN: 52436

Middle Eastern (MID) AF: 0.282 AC: 1624 AN: 5752

European-Non Finnish (NFE) AF: 0.305 AC: 336477 AN: 1103748

Other (OTH) AF: 0.299 AC: 17897 AN: 59842

GnomAD4 genome AF: 0.257 AC: 39122 AN: 152042 Hom.: 5539 Cov.: 33 AF XY: 0.258 AC XY: 19187 AN XY: 74304

African (AFR) AF: 0.142 AC: 5885 AN: 41508

American (AMR) AF: 0.264 AC: 4036 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1104 AN: 3470

East Asian (EAS) AF: 0.404 AC: 2071 AN: 5132

South Asian (SAS) AF: 0.280 AC: 1347 AN: 4818

European-Finnish (FIN) AF: 0.282 AC: 2983 AN: 10564

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20783 AN: 67956

Other (OTH) AF: 0.264 AC: 556 AN: 2108

Alfa AF: 0.284 Hom.: 16532

Bravo AF: 0.250

TwinsUK AF: 0.282 AC: 1046

ALSPAC AF: 0.297 AC: 1144

ESP6500AA AF: 0.148 AC: 649

ESP6500EA AF: 0.313 AC: 2688

ExAC AF: 0.272 AC: 32845

Asia WGS AF: 0.293 AC: 1018 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.065
DANN	Benign	0.67
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.00022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-1.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.60	N
REVEL	Benign	0.11
Sift	Benign	0.28	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.031
MPC		0.43
ClinPred		0.0075	T
GERP RS		-7.9
Varity_R		0.048
gMVP		0.39
Mutation Taster		=85/15	polymorphism (auto)

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: rs2230739; hg19: chr16-4033436; COSMIC: COSV53572353;