NM_183357.3:c.1135-23884C>T

Variant names:

• chr3-123376465-G-A
• rs6798189
• NM_183357.3:c.1135-23884C>T

Variant summary

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

The NM_183357.3(ADCY5):​c.1135-23884C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 151,978 control chromosomes in the GnomAD database, including 3,282 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 0.20 (3282 hom., cov: 31)
• Consequence: ADCY5 NM_183357.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.14
• Publications: 23 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=-0.72).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183357.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	NM_183357.3	MANE Select	c.1135-23884C>T		intron	N/A	NP_899200.1
	ADCY5	NM_001378259.1		c.1135-23884C>T		intron	N/A	NP_001365188.1
	ADCY5	NM_001199642.1		c.85-23884C>T		intron	N/A	NP_001186571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	ENST00000462833.6	TSL:1 MANE Select	c.1135-23884C>T		intron	N/A	ENSP00000419361.1
	ADCY5	ENST00000850916.1		c.1297-23884C>T		intron	N/A	ENSP00000520999.1
	ADCY5	ENST00000699718.1		c.1135-23884C>T		intron	N/A	ENSP00000514543.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29760 AN: 151860 Hom.: 3279 Cov.: 31

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.274

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.00271

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.177

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

GnomAD4 genome AF: 0.196 AC: 29772 AN: 151978 Hom.: 3282 Cov.: 31 AF XY: 0.193 AC XY: 14323 AN XY: 74282

African (AFR) AF: 0.117 AC: 4870 AN: 41460

American (AMR) AF: 0.274 AC: 4195 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 603 AN: 3466

East Asian (EAS) AF: 0.00272 AC: 14 AN: 5146

South Asian (SAS) AF: 0.205 AC: 983 AN: 4794

European-Finnish (FIN) AF: 0.175 AC: 1854 AN: 10568

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.245 AC: 16661 AN: 67950

Other (OTH) AF: 0.174 AC: 366 AN: 2106

Alfa AF: 0.224 Hom.: 7174

Bravo AF: 0.198

Asia WGS AF: 0.0930 AC: 324 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.9
DANN	Benign	0.87
PhyloP100		2.1
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: rs6798189; hg19: chr3-123095312;