Genetic Variant ADCY1:p.Ala78Ala (chr7-45574777-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_021116.4(ADCY1):c.234C>G(p.Ala78Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,493,600 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 18 hom., cov: 32)

Exomes 𝑓: 0.015 ( 212 hom. )

Consequence

ADCY1
NM_021116.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.386

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 7-45574777-C-G is Benign according to our data. Variant chr7-45574777-C-G is described in ClinVar as [Benign]. Clinvar id is 1238867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.386 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0149 (20040/1343204) while in subpopulation MID AF= 0.0369 (145/3930). AF 95% confidence interval is 0.032. There are 212 homozygotes in gnomad4_exome. There are 9681 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ADCY1	NM_021116.4 link	c.234C>G	p.Ala78Ala	synonymous_variant	Exon 1 of 20	ENST00000297323.12	NP_066939.1
ADCY1	XM_005249584.4 link	c.234C>G	p.Ala78Ala	synonymous_variant	Exon 1 of 19		XP_005249641.1
ADCY1	XM_005249585.3 link	c.234C>G	p.Ala78Ala	synonymous_variant	Exon 1 of 9		XP_005249642.1
ADCY1	NM_001281768.2 link	c.-330-112C>G		intron_variant	Intron 1 of 9		NP_001268697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADCY1	ENST00000297323.12 link	c.234C>G	p.Ala78Ala	synonymous_variant	Exon 1 of 20	1	NM_021116.4	ENSP00000297323.7	Q08828
ADCY1	ENST00000432715.5 link	c.-330-112C>G		intron_variant	Intron 1 of 9	2		ENSP00000392721.1	C9J1J0
ADCY1	ENST00000621543.1 link	c.-442C>G		upstream_gene_variant		5		ENSP00000479770.1	C9J1J0

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1943

AN:

150290

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00278

Gnomad AMI

AF:

0.0100

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.0457

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.00230

Gnomad FIN

AF:

0.0302

Gnomad MID

AF:

0.0461

Gnomad NFE

AF:

0.0158

Gnomad OTH

AF:

0.0219

GnomAD3 exomes

AF:

0.0153

AC:

1452

AN:

95198

Hom.:

AF XY:

0.0146

AC XY:

788

AN XY:

54058

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00940

Gnomad ASJ exome

AF:

0.0460

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00231

Gnomad FIN exome

AF:

0.0268

Gnomad NFE exome

AF:

0.0177

Gnomad OTH exome

AF:

0.0231

GnomAD4 exome

AF:

0.0149

AC:

20040

AN:

1343204

Hom.:

212

Cov.:

AF XY:

0.0146

AC XY:

9681

AN XY:

662890

show subpopulations

Gnomad4 AFR exome

AF:

0.00368

Gnomad4 AMR exome

AF:

0.0104

Gnomad4 ASJ exome

AF:

0.0455

Gnomad4 EAS exome

AF:

0.0000322

Gnomad4 SAS exome

AF:

0.00329

Gnomad4 FIN exome

AF:

0.0256

Gnomad4 NFE exome

AF:

0.0153

Gnomad4 OTH exome

AF:

0.0170

GnomAD4 genome

AF:

0.0129

AC:

1943

AN:

150396

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

969

AN XY:

73450

show subpopulations

Gnomad4 AFR

AF:

0.00277

Gnomad4 AMR

AF:

0.0144

Gnomad4 ASJ

AF:

0.0457

Gnomad4 EAS

AF:

0.000199

Gnomad4 SAS

AF:

0.00230

Gnomad4 FIN

AF:

0.0302

Gnomad4 NFE

AF:

0.0158

Gnomad4 OTH

AF:

0.0217

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.5

DANN

Benign

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over