chr3-123447965-C-CCCGAGT

Variant names:

• chr3-123447965-C-CCCGAGT
• rs1553751196
• NM_183357.3:c.575_580dupACTCGG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_001378259.1(ADCY5):​c.575_580dupACTCGG​(p.Asp192_Ser193dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000761 in 1,313,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: ADCY5 NM_001378259.1 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68
• 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, 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_001378259.1

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378259.1. 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.575_580dupACTCGG	p.Asp192_Ser193dup	conservative_inframe_insertion	Exon 1 of 21	NP_899200.1
	ADCY5	NM_001378259.1		c.575_580dupACTCGG	p.Asp192_Ser193dup	conservative_inframe_insertion	Exon 1 of 22	NP_001365188.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY5	ENST00000462833.6	TSL:1 MANE Select	c.575_580dupACTCGG	p.Asp192_Ser193dup	conservative_inframe_insertion	Exon 1 of 21	ENSP00000419361.1
	ADCY5	ENST00000850916.1		c.737_742dupACTCGG	p.Asp246_Ser247dup	conservative_inframe_insertion	Exon 1 of 21	ENSP00000520999.1
	ADCY5	ENST00000699718.1		c.575_580dupACTCGG	p.Asp192_Ser193dup	conservative_inframe_insertion	Exon 1 of 22	ENSP00000514543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1313596 Hom.: 0 Cov.: 29 AF XY: 0.00000156 AC XY: 1 AN XY: 643072

African (AFR) AF: 0.00 AC: 0 AN: 27716

American (AMR) AF: 0.00 AC: 0 AN: 24278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20338

East Asian (EAS) AF: 0.00 AC: 0 AN: 32046

South Asian (SAS) AF: 0.00 AC: 0 AN: 66172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5208

European-Non Finnish (NFE) AF: 9.61e-7 AC: 1 AN: 1040230

Other (OTH) AF: 0.00 AC: 0 AN: 53944

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

Splicing

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

Other links and lift over

dbSNP: rs1553751196; hg19: chr3-123166812;