rs78087585

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_021116.4(ADCY1):c.897C>T(p.His299His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,613,608 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0043 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 28 hom. )

Consequence

ADCY1
NM_021116.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.163

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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
autosomal recessive nonsyndromic hearing loss 44
Inheritance: AR, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ADCY1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 7-45610486-C-T is Benign according to our data. Variant chr7-45610486-C-T is described in ClinVar as Benign. ClinVar VariationId is 517530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.163 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 3 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ADCY1	NM_021116.4 link	c.897C>T	p.His299His	synonymous_variant	Exon 3 of 20	ENST00000297323.12	NP_066939.1
ADCY1	NM_001281768.2 link	c.222C>T	p.His74His	synonymous_variant	Exon 4 of 10		NP_001268697.1
ADCY1	XM_005249584.4 link	c.897C>T	p.His299His	synonymous_variant	Exon 3 of 19		XP_005249641.1
ADCY1	XM_005249585.3 link	c.897C>T	p.His299His	synonymous_variant	Exon 3 of 9		XP_005249642.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ADCY1	ENST00000297323.12 link	c.897C>T	p.His299His	synonymous_variant	Exon 3 of 20	1	NM_021116.4	ENSP00000297323.7
ADCY1	ENST00000432715.5 link	c.222C>T	p.His74His	synonymous_variant	Exon 4 of 10	2		ENSP00000392721.1
ADCY1	ENST00000621543.1 link	c.222C>T	p.His74His	synonymous_variant	Exon 3 of 9	5		ENSP00000479770.1

Frequencies

GnomAD3 genomes

AF:

0.00431

AC:

655

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00633

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.00952

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.000849

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00356

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00321

AC:

800

AN:

249252

AF XY:

0.00332

show subpopulations

Gnomad AFR exome

AF:

0.00621

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00351

Gnomad OTH exome

AF:

0.00507

GnomAD4 exome

AF:

0.00387

AC:

5655

AN:

1461432

Hom.:

Cov.:

AF XY:

0.00390

AC XY:

2838

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.00601

AC:

201

AN:

33472

American (AMR)

AF:

0.00295

AC:

132

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0111

AC:

291

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00279

AC:

241

AN:

86256

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

53278

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00386

AC:

4296

AN:

1111756

Other (OTH)

AF:

0.00586

AC:

354

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

269

538

808

1077

1346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<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:

0.00433

AC:

659

AN:

152176

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

302

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00641

AC:

266

AN:

41502

American (AMR)

AF:

0.00504

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00952

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5154

South Asian (SAS)

AF:

0.00249

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000849

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00356

AC:

242

AN:

68018

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

103

137

171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00473

Hom.:

Bravo

AF:

0.00494

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00474

EpiControl

AF:

0.00391

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 15, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.His299His in exon 3 of ADCY1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 0.62% (64/10396) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs78087585). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

3.6

(source)

DANN

Benign

0.79

PhyloP100

-0.16

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over