chr2-24824539-A-G

Variant names:

• chr2-24824539-A-G
• rs7604576
• NM_004036.5:c.2578-3T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004036.5(ADCY3):​c.2578-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,613,354 control chromosomes in the GnomAD database, including 228,070 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18952 hom., cov: 33)
  • Exomes 𝑓: 0.53 (209118 hom.)
• Consequence: ADCY3 NM_004036.5 splice_region, intron
• Scores: Splicing: ADA: 0.00003597
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.187
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-24824539-A-G is Benign according to our data. Variant chr2-24824539-A-G is described in ClinVar as Benign. ClinVar VariationId is 1598739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.642 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.2578-3T>C		splice_region intron	N/A	NP_004027.2	O60266-1
	ADCY3	NM_001377128.1		c.2644-3T>C		splice_region intron	N/A	NP_001364057.1
	ADCY3	NM_001320613.2		c.2581-3T>C		splice_region intron	N/A	NP_001307542.1	A0A0A0MSC1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY3	ENST00000679454.1	MANE Select	c.2578-3T>C		splice_region intron	N/A	ENSP00000505261.1	O60266-1
	ADCY3	ENST00000405392.6	TSL:1	c.2581-3T>C		splice_region intron	N/A	ENSP00000384484.2	A0A0A0MSC1
	ADCY3	ENST00000260600.9	TSL:1	c.2578-3T>C		splice_region intron	N/A	ENSP00000260600.5	O60266-1

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73490 AN: 152050 Hom.: 18939 Cov.: 33

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.516

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.508

GnomAD2 exomes AF: 0.551 AC: 138427 AN: 251200 AF XY: 0.548

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.747

Gnomad ASJ exome AF: 0.521

Gnomad EAS exome AF: 0.639

Gnomad FIN exome AF: 0.514

Gnomad NFE exome AF: 0.517

Gnomad OTH exome AF: 0.557

GnomAD4 exome AF: 0.531 AC: 775992 AN: 1461186 Hom.: 209118 Cov.: 43 AF XY: 0.532 AC XY: 386487 AN XY: 726860

African (AFR) AF: 0.288 AC: 9650 AN: 33460

American (AMR) AF: 0.736 AC: 32902 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 13711 AN: 26130

East Asian (EAS) AF: 0.655 AC: 26002 AN: 39680

South Asian (SAS) AF: 0.572 AC: 49298 AN: 86236

European-Finnish (FIN) AF: 0.507 AC: 27077 AN: 53358

Middle Eastern (MID) AF: 0.518 AC: 2985 AN: 5760

European-Non Finnish (NFE) AF: 0.524 AC: 582117 AN: 1111482

Other (OTH) AF: 0.534 AC: 32250 AN: 60370

GnomAD4 genome AF: 0.483 AC: 73518 AN: 152168 Hom.: 18952 Cov.: 33 AF XY: 0.488 AC XY: 36333 AN XY: 74398

African (AFR) AF: 0.308 AC: 12773 AN: 41510

American (AMR) AF: 0.643 AC: 9831 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.516 AC: 1791 AN: 3470

East Asian (EAS) AF: 0.660 AC: 3419 AN: 5178

South Asian (SAS) AF: 0.588 AC: 2834 AN: 4822

European-Finnish (FIN) AF: 0.500 AC: 5292 AN: 10584

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.529 AC: 35974 AN: 67994

Other (OTH) AF: 0.513 AC: 1085 AN: 2114

Alfa AF: 0.482 Hom.: 15932

Bravo AF: 0.486

Asia WGS AF: 0.645 AC: 2242 AN: 3478

EpiCase AF: 0.516

EpiControl AF: 0.528

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	-0.80
CADD	Benign	1.2
DANN	Benign	0.66
PhyloP100		-0.19
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0
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: rs7604576; hg19: chr2-25047408; COSMIC: COSV53165736; COSMIC: COSV53165736;