NM_183357.3:c.3689_3690delCCinsTT

Variant names:

• chr3-123284704-GG-AA
• NM_183357.3:c.3689_3690delCCinsTT
• ADCY5 p.Ala1230Val

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_183357.3(ADCY5):​c.3689_3690delCCinsTT​(p.Ala1230Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1230T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADCY5 NM_183357.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.71
• Publications: 0 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

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• 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: Orphanet, Ambry Genetics
• choreatic disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	NM_183357.3	MANE Select	c.3689_3690delCCinsTT	p.Ala1230Val	missense	N/A	NP_899200.1	O95622-1
	ADCY5	NM_001378259.1		c.3764_3765delCCinsTT	p.Ala1255Val	missense	N/A	NP_001365188.1	A0A8V8TP58
	ADCY5	NM_001199642.1		c.2639_2640delCCinsTT	p.Ala880Val	missense	N/A	NP_001186571.1	O95622-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	ENST00000462833.6	TSL:1 MANE Select	c.3689_3690delCCinsTT	p.Ala1230Val	missense	N/A	ENSP00000419361.1	O95622-1
	ADCY5	ENST00000850916.1		c.3851_3852delCCinsTT	p.Ala1284Val	missense	N/A	ENSP00000520999.1	A0ABJ7H376
	ADCY5	ENST00000699718.1		c.3764_3765delCCinsTT	p.Ala1255Val	missense	N/A	ENSP00000514543.1	A0A8V8TP58

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-123003551;