7-45574794-C-G

Position:

chr7-45574794-C-G

Variant summary

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

The NM_021116.4(ADCY1):c.251C>G(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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

ADCY1
NM_021116.4 missense

Scores

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]

ADCY1 links:

Genome browser will be placed here

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 in gene, where missense usually causes diseases (based on misZ statistic), ADCY1. . Gene score misZ 4.3801 (greater than the threshold 3.09). Trascript score misZ 4.6991 (greater than threshold 3.09). GenCC has associacion of gene with hearing loss, autosomal recessive, autosomal recessive nonsyndromic hearing loss 44.

BP4

Computational evidence support a benign effect (MetaRNN=0.352872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ADCY1	NM_021116.4 linkuse as main transcript	c.251C>G	p.Pro84Arg	missense_variant	1/20	ENST00000297323.12	NP_066939.1
ADCY1	XM_005249584.4 linkuse as main transcript	c.251C>G	p.Pro84Arg	missense_variant	1/19		XP_005249641.1
ADCY1	XM_005249585.3 linkuse as main transcript	c.251C>G	p.Pro84Arg	missense_variant	1/9		XP_005249642.1
ADCY1	NM_001281768.2 linkuse as main transcript	c.-330-95C>G		intron_variant			NP_001268697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY1	ENST00000297323.12 linkuse as main transcript	c.251C>G	p.Pro84Arg	missense_variant	1/20	1	NM_021116.4	ENSP00000297323	P1
ADCY1	ENST00000432715.5 linkuse as main transcript	c.-330-95C>G		intron_variant		2		ENSP00000392721

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000599

AC:

AN:

166988

Hom.:

AF XY:

0.0000106

AC XY:

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:

AN:

1405456

Hom.:

Cov.:

AF XY:

0.00000287

AC XY:

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.:

Alfa

AF:

0.0000468

Hom.:

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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 27, 2023

This 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

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.35

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.82

D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.47

REVEL

Uncertain

0.29

Sift

Benign

0.31

Sift4G

Benign

0.35

Polyphen

0.97

Vest4

0.26

MutPred

0.47

Gain of methylation at P84 (P = 0.0102);

MVP

0.71

MPC

2.2

ClinPred

0.38

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.

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