NM_021116.4:c.32_43delGCGGAGGCGGCG

Variant names:

• chr7-45574559-CGCGGCGGAGGCG-C
• rs968371618
• NM_021116.4:c.32_43delGCGGAGGCGGCG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_021116.4(ADCY1):​c.32_43delGCGGAGGCGGCG​(p.Gly11_Gly14del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 977,018 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ADCY1 NM_021116.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64
• Publications: 1 publications found

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]

ADCY1 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 44

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_021116.4.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021116.4. 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
	ADCY1	NM_021116.4	MANE Select	c.32_43delGCGGAGGCGGCG	p.Gly11_Gly14del	disruptive_inframe_deletion	Exon 1 of 20	NP_066939.1	Q08828
	ADCY1	NM_001281768.2		c.-330-314_-330-303delGCGGAGGCGGCG		intron	N/A	NP_001268697.1	C9J1J0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY1	ENST00000297323.12	TSL:1 MANE Select	c.32_43delGCGGAGGCGGCG	p.Gly11_Gly14del	disruptive_inframe_deletion	Exon 1 of 20	ENSP00000297323.7	Q08828
	ADCY1	ENST00000920696.1		c.32_43delGCGGAGGCGGCG	p.Gly11_Gly14del	disruptive_inframe_deletion	Exon 1 of 19	ENSP00000590755.1
	ADCY1	ENST00000432715.5	TSL:2	c.-330-314_-330-303delGCGGAGGCGGCG		intron	N/A	ENSP00000392721.1	C9J1J0

Frequencies

GnomAD3 genomes AF: 0.000314 AC: 45 AN: 143096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000402

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000825

Gnomad ASJ AF: 0.00119

Gnomad EAS AF: 0.000417

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000139

Gnomad OTH AF: 0.00100

GnomAD4 exome AF: 0.000108 AC: 90 AN: 833886 Hom.: 0 AF XY: 0.000117 AC XY: 45 AN XY: 385172

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000253 AC: 4 AN: 15786

American (AMR) AF: 0.00 AC: 0 AN: 998

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 6 AN: 5160

East Asian (EAS) AF: 0.000275 AC: 1 AN: 3630

South Asian (SAS) AF: 0.0000589 AC: 1 AN: 16972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1620

European-Non Finnish (NFE) AF: 0.0000919 AC: 70 AN: 762098

Other (OTH) AF: 0.000293 AC: 8 AN: 27328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000314 AC: 45 AN: 143132 Hom.: 0 Cov.: 31 AF XY: 0.000287 AC XY: 20 AN XY: 69580

African (AFR) AF: 0.000401 AC: 16 AN: 39854

American (AMR) AF: 0.000824 AC: 12 AN: 14564

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 4 AN: 3354

East Asian (EAS) AF: 0.000419 AC: 2 AN: 4778

South Asian (SAS) AF: 0.00 AC: 0 AN: 4666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000139 AC: 9 AN: 64794

Other (OTH) AF: 0.000995 AC: 2 AN: 2010

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000246

ClinVar

ClinVar submissions

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		2.6
Mutation Taster		=181/19	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs968371618; hg19: chr7-45614158;