2-24823221-T-C

Variant names:

• chr2-24823221-T-C
• rs1127568
• NM_004036.5:c.2871A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004036.5(ADCY3):​c.2871A>G​(p.Ser957Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,611,864 control chromosomes in the GnomAD database, including 371,410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32642 hom., cov: 32)
  • Exomes 𝑓: 0.68 (338768 hom.)
• Consequence: ADCY3 NM_004036.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.32
• Publications: 25 publications found

Genes affected

ADCY3 (HGNC:234): (adenylate cyclase 3) This gene encodes adenylyl cyclase 3 which is a membrane-associated enzyme and catalyzes the formation of the secondary messenger cyclic adenosine monophosphate (cAMP). This protein appears to be widely expressed in various human tissues and may be involved in a number of physiological and pathophysiological metabolic processes. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

ADCY3 Gene-Disease associations (from GenCC):

• body mass index quantitative trait locus 19

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 2-24823221-T-C is Benign according to our data. Variant chr2-24823221-T-C is described in ClinVar as Benign. ClinVar VariationId is 1641173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004036.5. 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
	ADCY3	NM_004036.5	MANE Select	c.2871A>G	p.Ser957Ser	synonymous	Exon 18 of 22	NP_004027.2	O60266-1
	ADCY3	NM_001377128.1		c.2937A>G	p.Ser979Ser	synonymous	Exon 19 of 23	NP_001364057.1
	ADCY3	NM_001320613.2		c.2874A>G	p.Ser958Ser	synonymous	Exon 18 of 22	NP_001307542.1	A0A0A0MSC1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY3	ENST00000679454.1	MANE Select	c.2871A>G	p.Ser957Ser	synonymous	Exon 18 of 22	ENSP00000505261.1	O60266-1
	ADCY3	ENST00000405392.6	TSL:1	c.2874A>G	p.Ser958Ser	synonymous	Exon 17 of 21	ENSP00000384484.2	A0A0A0MSC1
	ADCY3	ENST00000260600.9	TSL:1	c.2871A>G	p.Ser957Ser	synonymous	Exon 17 of 21	ENSP00000260600.5	O60266-1

Frequencies

GnomAD3 genomes AF: 0.650 AC: 98760 AN: 151934 Hom.: 32628 Cov.: 32

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.774

Gnomad ASJ AF: 0.643

Gnomad EAS AF: 0.875

Gnomad SAS AF: 0.693

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.684

GnomAD2 exomes AF: 0.694 AC: 173780 AN: 250322 AF XY: 0.690

Gnomad AFR exome AF: 0.533

Gnomad AMR exome AF: 0.849

Gnomad ASJ exome AF: 0.657

Gnomad EAS exome AF: 0.854

Gnomad FIN exome AF: 0.660

Gnomad NFE exome AF: 0.659

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.679 AC: 991473 AN: 1459812 Hom.: 338768 Cov.: 51 AF XY: 0.679 AC XY: 492699 AN XY: 726138

African (AFR) AF: 0.523 AC: 17478 AN: 33406

American (AMR) AF: 0.841 AC: 37393 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.658 AC: 17177 AN: 26112

East Asian (EAS) AF: 0.877 AC: 34782 AN: 39666

South Asian (SAS) AF: 0.677 AC: 58294 AN: 86080

European-Finnish (FIN) AF: 0.656 AC: 35009 AN: 53390

Middle Eastern (MID) AF: 0.672 AC: 3400 AN: 5058

European-Non Finnish (NFE) AF: 0.672 AC: 746523 AN: 1111398

Other (OTH) AF: 0.687 AC: 41417 AN: 60264

GnomAD4 genome AF: 0.650 AC: 98817 AN: 152052 Hom.: 32642 Cov.: 32 AF XY: 0.654 AC XY: 48611 AN XY: 74328

African (AFR) AF: 0.535 AC: 22180 AN: 41446

American (AMR) AF: 0.774 AC: 11830 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.643 AC: 2233 AN: 3472

East Asian (EAS) AF: 0.875 AC: 4527 AN: 5176

South Asian (SAS) AF: 0.693 AC: 3343 AN: 4826

European-Finnish (FIN) AF: 0.654 AC: 6914 AN: 10566

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.671 AC: 45590 AN: 67972

Other (OTH) AF: 0.687 AC: 1450 AN: 2112

Alfa AF: 0.664 Hom.: 65467

Bravo AF: 0.657

Asia WGS AF: 0.780 AC: 2713 AN: 3478

EpiCase AF: 0.664

EpiControl AF: 0.676

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
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.058
DANN	Benign	0.62
PhyloP100		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=64/36	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: rs1127568; hg19: chr2-25046090; COSMIC: COSV105021005; COSMIC: COSV105021005;