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GeneBe

7-45574794-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_021116.4(ADCY1):ā€‹c.251C>Gā€‹(p.Pro84Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000356 in 1,405,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000036 ( 0 hom. )

Consequence

ADCY1
NM_021116.4 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.09
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, ADCY1
BP4
Computational evidence support a benign effect (MetaRNN=0.352872).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ADCY1NM_021116.4 linkuse as main transcriptc.251C>G p.Pro84Arg missense_variant 1/20 ENST00000297323.12
ADCY1XM_005249584.4 linkuse as main transcriptc.251C>G p.Pro84Arg missense_variant 1/19
ADCY1XM_005249585.3 linkuse as main transcriptc.251C>G p.Pro84Arg missense_variant 1/9
ADCY1NM_001281768.2 linkuse as main transcriptc.-330-95C>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ADCY1ENST00000297323.12 linkuse as main transcriptc.251C>G p.Pro84Arg missense_variant 1/201 NM_021116.4 P1
ADCY1ENST00000432715.5 linkuse as main transcriptc.-330-95C>G intron_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000599
AC:
1
AN:
166988
Hom.:
0
AF XY:
0.0000106
AC XY:
1
AN XY:
94130
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000138
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000356
AC:
5
AN:
1405456
Hom.:
0
Cov.:
31
AF XY:
0.00000287
AC XY:
2
AN XY:
697174
show subpopulations
Gnomad4 AFR exome
AF:
0.0000344
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000367
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000468
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 27, 2023This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 84 of the ADCY1 protein (p.Pro84Arg). This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with ADCY1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADCY1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
0.0043
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.21
T
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.50
T
M_CAP
Pathogenic
0.46
D
MetaRNN
Benign
0.35
T
MetaSVM
Benign
-0.74
T
MutationAssessor
Benign
1.8
L
MutationTaster
Benign
0.82
D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
0.47
N
REVEL
Uncertain
0.29
Sift
Benign
0.31
T
Sift4G
Benign
0.35
T
Polyphen
0.97
D
Vest4
0.26
MutPred
0.47
Gain of methylation at P84 (P = 0.0102);
MVP
0.71
MPC
2.2
ClinPred
0.38
T
GERP RS
2.7
Varity_R
0.11
gMVP
0.17

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.

Other links and lift over

dbSNP: rs1379522327; hg19: chr7-45614393; API