3-123375604-T-C

Variant names:

• chr3-123375604-T-C
• rs2877716
• NM_183357.3:c.1135-23023A>G

Variant summary

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

The NM_183357.3(ADCY5):​c.1135-23023A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.765 in 152,232 control chromosomes in the GnomAD database, including 44,783 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.77 (44783 hom., cov: 34)
• Consequence: ADCY5 NM_183357.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.734
• Publications: 65 publications found

Genes affected

ADCY5 (HGNC:236): (adenylate cyclase 5) This gene encodes a member of the membrane-bound adenylyl cyclase enzymes. Adenylyl cyclases mediate G protein-coupled receptor signaling through the synthesis of the second messenger cAMP. Activity of the encoded protein is stimulated by the Gs alpha subunit of G protein-coupled receptors and is inhibited by protein kinase A, calcium and Gi alpha subunits. Single nucleotide polymorphisms in this gene may be associated with low birth weight and type 2 diabetes. Alternatively spliced transcript variants that encode different isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

ADCY5 Gene-Disease associations (from GenCC):

• dyskinesia with orofacial involvement, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P
• neurodevelopmental disorder with hyperkinetic movements and dyskinesia

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial dyskinesia and facial myokymia

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• choreatic disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY5	NM_183357.3	c.1135-23023A>G		intron_variant	Intron 1 of 20	ENST00000462833.6	NP_899200.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY5	ENST00000462833.6	c.1135-23023A>G		intron_variant	Intron 1 of 20	1	NM_183357.3	ENSP00000419361.1

Frequencies

GnomAD3 genomes AF: 0.765 AC: 116388 AN: 152114 Hom.: 44754 Cov.: 34

Gnomad AFR AF: 0.748

Gnomad AMI AF: 0.824

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.794

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.754

Gnomad OTH AF: 0.795

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.765 AC: 116467 AN: 152232 Hom.: 44783 Cov.: 34 AF XY: 0.771 AC XY: 57357 AN XY: 74436

African (AFR) AF: 0.748 AC: 31047 AN: 41520

American (AMR) AF: 0.708 AC: 10835 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.826 AC: 2869 AN: 3472

East Asian (EAS) AF: 0.997 AC: 5164 AN: 5178

South Asian (SAS) AF: 0.794 AC: 3834 AN: 4826

European-Finnish (FIN) AF: 0.824 AC: 8746 AN: 10612

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.754 AC: 51292 AN: 68004

Other (OTH) AF: 0.798 AC: 1688 AN: 2116

Alfa AF: 0.761 Hom.: 199773

Bravo AF: 0.757

Asia WGS AF: 0.897 AC: 3119 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.7
DANN	Benign	0.64
PhyloP100		-0.73
Mutation Taster		=100/0	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: rs2877716; hg19: chr3-123094451;