rs2293106

Positions:

• chr7-45713725-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021116.4(ADCY1):​c.3090G>A​(p.Arg1030=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 780,528 control chromosomes in the GnomAD database, including 11,205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3429 hom., cov: 33)
  • Exomes 𝑓: 0.15 (7776 hom.)
• Consequence: ADCY1 NM_021116.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.63

Genes affected

ADCY1 (HGNC:232): (adenylate cyclase 1) This gene encodes a member of the of adenylate cyclase gene family that is primarily expressed in the brain. This protein is regulated by calcium/calmodulin concentration and may be involved in brain development. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-45713725-G-A is Benign according to our data. Variant chr7-45713725-G-A is described in ClinVar as [Benign]. Clinvar id is 517532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY1	NM_021116.4	c.3090G>A	p.Arg1030=	synonymous_variant	20/20	ENST00000297323.12
ADCY1	XM_005249584.4	c.*25G>A		3_prime_UTR_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY1	ENST00000297323.12	c.3090G>A	p.Arg1030=	synonymous_variant	20/20	1	NM_021116.4	P1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29976 AN: 152158 Hom.: 3425 Cov.: 33

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0434

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.209

GnomAD3 exomes AF: 0.147 AC: 36842 AN: 251350 Hom.: 3315 AF XY: 0.142 AC XY: 19331 AN XY: 135856

Gnomad AFR exome AF: 0.317

Gnomad AMR exome AF: 0.0990

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.110

Gnomad SAS exome AF: 0.0451

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.145 AC: 91302 AN: 628252 Hom.: 7776 Cov.: 0 AF XY: 0.140 AC XY: 48050 AN XY: 342276

Gnomad4 AFR exome AF: 0.316

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.0777

Gnomad4 SAS exome AF: 0.0444

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.166

Gnomad4 OTH exome AF: 0.164

GnomAD4 genome AF: 0.197 AC: 29989 AN: 152276 Hom.: 3429 Cov.: 33 AF XY: 0.192 AC XY: 14318 AN XY: 74454

Gnomad4 AFR AF: 0.315

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.0424

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.212

Alfa AF: 0.185 Hom.: 1262

Bravo AF: 0.208

Asia WGS AF: 0.0900 AC: 319 AN: 3478

EpiCase AF: 0.177

EpiControl AF: 0.183

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 44 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Arg1030Arg in exon 20 of ADCY1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 31.47% (3265/10374 ) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs2293106). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	7.2
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2293106; hg19: chr7-45753324; COSMIC: COSV52040452;