Genetic Variant ADCY1:p.Gly11_Gly14dup (chr7-45574559-C-CGCGGCGGAGGCG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_021116.4(ADCY1):c.32_43dupGCGGAGGCGGCG(p.Gly11_Gly14dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000368 in 977,022 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 INS_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 0.000070 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

ADCY1
NM_021116.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.19

Publications

1 publications found

Variant links:

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)

ADCY1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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_43dupGCGGAGGCGGCG	p.Gly11_Gly14dup	disruptive_inframe_insertion	Exon 1 of 20	NP_066939.1	Q08828
	ADCY1	NM_001281768.2		c.-330-314_-330-303dupGCGGAGGCGGCG		intron	N/A	NP_001268697.1	C9J1J0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADCY1	ENST00000297323.12	TSL:1 MANE Select	c.32_43dupGCGGAGGCGGCG	p.Gly11_Gly14dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000297323.7	Q08828
ADCY1	ENST00000920696.1		c.32_43dupGCGGAGGCGGCG	p.Gly11_Gly14dup	disruptive_inframe_insertion	Exon 1 of 19	ENSP00000590755.1
ADCY1	ENST00000432715.5	TSL:2	c.-330-314_-330-303dupGCGGAGGCGGCG		intron	N/A	ENSP00000392721.1	C9J1J0

Frequencies

GnomAD3 genomes

AF:

0.0000769

AC:

AN:

143096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000503

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000687

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00125

Gnomad SAS

AF:

0.000427

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000312

AC:

AN:

833890

Hom.:

Cov.:

AF XY:

0.0000312

AC XY:

AN XY:

385172

show subpopulations

African (AFR)

AF:

0.000127

AC:

AN:

15786

American (AMR)

AF:

0.00

AC:

AN:

998

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5160

East Asian (EAS)

AF:

0.00110

AC:

AN:

3630

South Asian (SAS)

AF:

0.000177

AC:

AN:

16972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1620

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

762102

Other (OTH)

AF:

0.000146

AC:

AN:

27328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000699

AC:

AN:

143132

Hom.:

Cov.:

AF XY:

0.0000719

AC XY:

AN XY:

69580

show subpopulations

African (AFR)

AF:

0.0000502

AC:

AN:

39854

American (AMR)

AF:

0.0000687

AC:

AN:

14564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3354

East Asian (EAS)

AF:

0.00126

AC:

AN:

4778

South Asian (SAS)

AF:

0.000214

AC:

AN:

4666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7942

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64794

Other (OTH)

AF:

0.00

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.593

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=88/12

polymorphism

(source)

Splicing

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

Publications

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7-45574559-CGCGGCGGAGGCG-CGCGGCGGAGGCGGCGGCGGAGGCG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over