7-45574806-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021116.4(ADCY1):c.263C>T(p.Pro88Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,588,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ADCY1
NM_021116.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.179

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08877033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ADCY1	NM_021116.4 link	c.263C>T	p.Pro88Leu	missense_variant	Exon 1 of 20	ENST00000297323.12	NP_066939.1
ADCY1	XM_005249584.4 link	c.263C>T	p.Pro88Leu	missense_variant	Exon 1 of 19		XP_005249641.1
ADCY1	XM_005249585.3 link	c.263C>T	p.Pro88Leu	missense_variant	Exon 1 of 9		XP_005249642.1
ADCY1	NM_001281768.2 link	c.-330-83C>T		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.263C>T	p.Pro88Leu	missense_variant	Exon 1 of 20	1	NM_021116.4	ENSP00000297323.7	Q08828
ADCY1	ENST00000432715.5 link	c.-330-83C>T		intron_variant	Intron 1 of 9	2		ENSP00000392721.1	C9J1J0
ADCY1	ENST00000621543.1 link	c.-413C>T		upstream_gene_variant		5		ENSP00000479770.1	C9J1J0

Frequencies

GnomAD3 genomes

AF:

0.0000726

AC:

AN:

151514

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000722

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000289

AC:

AN:

207746

Hom.:

AF XY:

0.0000172

AC XY:

AN XY:

116272

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000188

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1436642

Hom.:

Cov.:

AF XY:

0.00000980

AC XY:

AN XY:

714224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000210

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.00000362

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.0000726

AC:

AN:

151514

Hom.:

Cov.:

AF XY:

0.0000946

AC XY:

AN XY:

73986

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000722

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ExAC

AF:

0.0000168

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 88 of the ADCY1 protein (p.Pro88Leu). This variant is present in population databases (rs770682134, gnomAD 0.02%). 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

0.098

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.21

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.64

MetaRNN

Benign

0.089

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.10

REVEL

Benign

0.16

Sift

Benign

0.66

Sift4G

Benign

0.67

Polyphen

0.0

Vest4

0.12

MutPred

0.36

Loss of loop (P = 0.0128);

MVP

0.38

MPC

1.3

ClinPred

0.029

GERP RS

2.8

Varity_R

0.039

gMVP

0.15

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