rs61729596

Positions:

• chr7-45662163-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000297323.12(ADCY1):​c.1554C>T​(p.Phe518=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0208 in 1,613,988 control chromosomes in the GnomAD database, including 444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (31 hom., cov: 32)
  • Exomes 𝑓: 0.021 (413 hom.)
• Consequence: ADCY1 ENST00000297323.12 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.70

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 7-45662163-C-T is Benign according to our data. Variant chr7-45662163-C-T is described in ClinVar as [Benign]. Clinvar id is 517531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0155 (2359/152284) while in subpopulation NFE AF= 0.0241 (1640/68030). AF 95% confidence interval is 0.0231. There are 31 homozygotes in gnomad4. There are 1190 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY1	NM_021116.4	c.1554C>T	p.Phe518=	synonymous_variant	8/20	ENST00000297323.12	NP_066939.1
ADCY1	NM_001281768.2	c.879C>T	p.Phe293=	synonymous_variant	9/10		NP_001268697.1
ADCY1	XM_005249584.4	c.1554C>T	p.Phe518=	synonymous_variant	8/19		XP_005249641.1
ADCY1	XM_005249585.3	c.1554C>T	p.Phe518=	synonymous_variant	8/9		XP_005249642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY1	ENST00000297323.12	c.1554C>T	p.Phe518=	synonymous_variant	8/20	1	NM_021116.4	ENSP00000297323	P1
ADCY1	ENST00000432715.5	c.879C>T	p.Phe293=	synonymous_variant	9/10	2		ENSP00000392721
ADCY1	ENST00000621543.1	c.879C>T	p.Phe293=	synonymous_variant	8/9	5		ENSP00000479770
ADCY1	ENST00000646653.1	n.495C>T		non_coding_transcript_exon_variant	4/8

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2362 AN: 152166 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0180 AC: 4523 AN: 251098 Hom.: 65 AF XY: 0.0192 AC XY: 2607 AN XY: 135716

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.00695

Gnomad ASJ exome AF: 0.00904

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0254

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0213 AC: 31207 AN: 1461704 Hom.: 413 Cov.: 31 AF XY: 0.0217 AC XY: 15807 AN XY: 727152

Gnomad4 AFR exome AF: 0.00343

Gnomad4 AMR exome AF: 0.00722

Gnomad4 ASJ exome AF: 0.00899

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0263

Gnomad4 FIN exome AF: 0.0269

Gnomad4 NFE exome AF: 0.0230

Gnomad4 OTH exome AF: 0.0187

GnomAD4 genome AF: 0.0155 AC: 2359 AN: 152284 Hom.: 31 Cov.: 32 AF XY: 0.0160 AC XY: 1190 AN XY: 74454

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.0241

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0196 Hom.: 8

Bravo AF: 0.0130

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.0243

EpiControl AF: 0.0222

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Phe518Phe in exon 8 of ADCY1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 2.67% (420/15720) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs61729596). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs61729596; hg19: chr7-45701762;