1-167809757-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018417.6(ADCY10):c.4754T>C(p.Val1585Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,614,064 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 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: ADCY10 NM_018417.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0390

Genes affected

ADCY10 (HGNC:21285): (adenylate cyclase 10) The protein encoded by this gene belongs to a distinct class of adenylyl cyclases that is soluble and insensitive to G protein or forskolin regulation. Activity of this protein is regulated by bicarbonate. Variation at this gene has been observed in patients with absorptive hypercalciuria. Alternatively spliced transcript variants encoding different isoforms have been observed. There is a pseudogene of this gene on chromosome 6. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01853484).
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY10	NM_018417.6	c.4754T>C	p.Val1585Ala	missense_variant	33/33	ENST00000367851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY10	ENST00000367851.9	c.4754T>C	p.Val1585Ala	missense_variant	33/33	1	NM_018417.6	P1
ADCY10	ENST00000367848.1	c.4478T>C	p.Val1493Ala	missense_variant	33/33	1
ADCY10	ENST00000545172.5	c.4295T>C	p.Val1432Ala	missense_variant	30/30	2
ADCY10	ENST00000485964.5	c.*1690T>C		3_prime_UTR_variant, NMD_transcript_variant	15/15	5

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251438 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135892

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: 0.00106

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.0000715 AC XY: 52 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000299

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: 0.000992

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000918 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.00

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2023

The c.4754T>C (p.V1585A) alteration is located in exon 33 (coding exon 32) of the ADCY10 gene. This alteration results from a T to C substitution at nucleotide position 4754, causing the valine (V) at amino acid position 1585 to be replaced by an alanine (A). 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

Apr 12, 2022

This variant is present in population databases (rs201210676, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1585 of the ADCY10 protein (p.Val1585Ala). This variant has not been reported in the literature in individuals affected with ADCY10-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine 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	0.076
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.10
Dann	Benign	0.75
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.47	T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.019	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.15	N;N;N
REVEL	Benign	0.013
Sift	Benign	0.13	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.16, 0.24	.;B;B
Vest4		0.091
MutPred		0.27		.;Loss of sheet (P = 0.0142);.;
MVP		0.15
MPC		0.14
ClinPred		0.040	T
GERP RS		-0.073
Varity_R		0.045
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: rs201210676; hg19: chr1-167778994; COSMIC: COSV63241859;