7-45574643-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_021116.4(ADCY1):c.100C>G(p.Arg34Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000602 in 1,260,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: ADCY1 NM_021116.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.73

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 Likely_benign. Variant got -1 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=0.0038677454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY1	NM_021116.4	c.100C>G	p.Arg34Gly	missense_variant	1/20	ENST00000297323.12
ADCY1	XM_005249584.4	c.100C>G	p.Arg34Gly	missense_variant	1/19
ADCY1	XM_005249585.3	c.100C>G	p.Arg34Gly	missense_variant	1/9
ADCY1	NM_001281768.2	c.-330-246C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY1	ENST00000297323.12	c.100C>G	p.Arg34Gly	missense_variant	1/20	1	NM_021116.4	P1
ADCY1	ENST00000432715.5	c.-330-246C>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000275 AC: 41 AN: 149326 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000974

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: 0.000317

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000491

Gnomad OTH AF: 0.000486

GnomAD3 exomes AF: 0.000695 AC: 6 AN: 8636 Hom.: 0 AF XY: 0.000540 AC XY: 3 AN XY: 5558

Gnomad AFR exome AF: 0.00781

Gnomad AMR exome AF: 0.00115

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: 0.00114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000646 AC: 718 AN: 1110898 Hom.: 0 Cov.: 30 AF XY: 0.000626 AC XY: 333 AN XY: 532032

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000121

Gnomad4 NFE exome AF: 0.000743

Gnomad4 OTH exome AF: 0.000317

GnomAD4 genome AF: 0.000274 AC: 41 AN: 149428 Hom.: 0 Cov.: 32 AF XY: 0.000206 AC XY: 15 AN XY: 72938

Gnomad4 AFR AF: 0.0000972

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000317

Gnomad4 NFE AF: 0.000491

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000332

ExAC AF: 0.0000820 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.100C>G (p.R34G) alteration is located in exon 1 (coding exon 1) of the ADCY1 gene. This alteration results from a C to G substitution at nucleotide position 100, causing the arginine (R) at amino acid position 34 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2023

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 34 of the ADCY1 protein (p.Arg34Gly). This variant is present in population databases (rs760606743, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ADCY1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1988548). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	0.062
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	20
Dann	Benign	0.87
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.24
Sift	Benign	0.39	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.45		Loss of MoRF binding (P = 0.0092);
MVP		0.37
MPC		1.6
ClinPred		0.012	T
GERP RS		-0.38
Varity_R		0.14
gMVP		0.23

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: rs760606743; hg19: chr7-45614242;