rs116510137

chr1-167833038-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018417.6(ADCY10):c.3542A>G(p.Asn1181Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,614,096 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (28 hom.)
• Consequence: ADCY10 NM_018417.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.523

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034321547).
• BP6: Variant 1-167833038-T-C is Benign according to our data. Variant chr1-167833038-T-C is described in ClinVar as [Benign]. Clinvar id is 402343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1954/152226) while in subpopulation AFR AF= 0.0445 (1849/41544). AF 95% confidence interval is 0.0428. There are 41 homozygotes in gnomad4. There are 915 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1952 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY10	NM_018417.6	c.3542A>G	p.Asn1181Ser	missense_variant	25/33	ENST00000367851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY10	ENST00000367851.9	c.3542A>G	p.Asn1181Ser	missense_variant	25/33	1	NM_018417.6	P1
ADCY10	ENST00000367848.1	c.3266A>G	p.Asn1089Ser	missense_variant	25/33	1
ADCY10	ENST00000545172.5	c.3083A>G	p.Asn1028Ser	missense_variant	22/30	2
ADCY10	ENST00000485964.5	c.*428A>G		3_prime_UTR_variant, NMD_transcript_variant	6/15	5

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1952 AN: 152108 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00383 AC: 963 AN: 251452 Hom.: 16 AF XY: 0.00276 AC XY: 375 AN XY: 135902

Gnomad AFR exome AF: 0.0471

Gnomad AMR exome AF: 0.00431

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00137 AC: 1996 AN: 1461870 Hom.: 28 Cov.: 32 AF XY: 0.00114 AC XY: 832 AN XY: 727240

Gnomad4 AFR exome AF: 0.0430

Gnomad4 AMR exome AF: 0.00454

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00275

GnomAD4 genome AF: 0.0128 AC: 1954 AN: 152226 Hom.: 41 Cov.: 32 AF XY: 0.0123 AC XY: 915 AN XY: 74420

Gnomad4 AFR AF: 0.0445

Gnomad4 AMR AF: 0.00524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00226 Hom.: 7

Bravo AF: 0.0150

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0409 AC: 180

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00468 AC: 568

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	4.3
Dann	Benign	0.83
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.83	N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.022
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0060, 0.010	.;B;B
Vest4		0.23
MVP		0.18
MPC		0.091
ClinPred		0.0013	T
GERP RS		3.0
Varity_R		0.030
gMVP		0.083

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: rs116510137; hg19: chr1-167802276;