Genetic Variant ADCY1:p.Arg30Trp (chr7-45574631-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_021116.4(ADCY1):c.88C>T(p.Arg30Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,200,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ADCY1
NM_021116.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.30

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2892139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ADCY1	NM_021116.4 link	c.88C>T	p.Arg30Trp	missense_variant	Exon 1 of 20	ENST00000297323.12	NP_066939.1
ADCY1	XM_005249584.4 link	c.88C>T	p.Arg30Trp	missense_variant	Exon 1 of 19		XP_005249641.1
ADCY1	XM_005249585.3 link	c.88C>T	p.Arg30Trp	missense_variant	Exon 1 of 9		XP_005249642.1
ADCY1	NM_001281768.2 link	c.-330-258C>T		intron_variant	Intron 1 of 9		NP_001268697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY1	ENST00000297323.12 link	c.88C>T	p.Arg30Trp	missense_variant	Exon 1 of 20	1	NM_021116.4	ENSP00000297323.7		Q08828
ADCY1	ENST00000432715.5 link	c.-330-258C>T		intron_variant	Intron 1 of 9	2		ENSP00000392721.1		C9J1J0

Frequencies

GnomAD3 genomes

AF:

0.0000204

AC:

AN:

146754

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000302

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000142

AC:

AN:

1054168

Hom.:

Cov.:

AF XY:

0.0000160

AC XY:

AN XY:

498948

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000155

Gnomad4 OTH exome

AF:

0.0000243

GnomAD4 genome

AF:

0.0000204

AC:

AN:

146754

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71530

show subpopulations

Gnomad4 AFR

AF:

0.0000248

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000302

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 30 of the ADCY1 protein (p.Arg30Trp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ADCY1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.19

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.0

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-1.7

REVEL

Benign

0.23

Sift

Benign

0.041

Sift4G

Uncertain

0.017

Polyphen

0.013

Vest4

0.12

MutPred

0.33

Loss of helix (P = 0.0558);

MVP

0.43

MPC

1.7

ClinPred

0.37

GERP RS

1.4

Varity_R

0.073

gMVP

0.38

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