7-45574632-G-C

Position:

• chr7-45574632-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_021116.4(ADCY1):​c.89G>C​(p.Arg30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY1 NM_021116.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.494

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY1	NM_021116.4	c.89G>C	p.Arg30Pro	missense_variant	1/20	ENST00000297323.12	NP_066939.1
ADCY1	XM_005249584.4	c.89G>C	p.Arg30Pro	missense_variant	1/19		XP_005249641.1
ADCY1	XM_005249585.3	c.89G>C	p.Arg30Pro	missense_variant	1/9		XP_005249642.1
ADCY1	NM_001281768.2	c.-330-257G>C		intron_variant			NP_001268697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY1	ENST00000297323.12	c.89G>C	p.Arg30Pro	missense_variant	1/20	1	NM_021116.4	ENSP00000297323	P1
ADCY1	ENST00000432715.5	c.-330-257G>C		intron_variant		2		ENSP00000392721

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with ADCY1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 30 of the ADCY1 protein (p.Arg30Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.79	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.35
Sift	Benign	0.15	T
Sift4G	Benign	0.27	T
Polyphen		0.98	D
Vest4		0.13
MutPred		0.28		Loss of MoRF binding (P = 0.0012);
MVP		0.81
MPC		1.7
ClinPred		0.39	T
GERP RS		2.4
Varity_R		0.32
gMVP		0.41

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

Other links and lift over

dbSNP: rs1439485446; hg19: chr7-45614231;