rs116510137

Variant names:

• chr1-167833038-T-C
• rs116510137
• NM_018417.6:c.3542A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:3
• Conservation: PhyloP100: 0.523
• Publications: 4 publications found

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]

ADCY10 Gene-Disease associations (from GenCC):

• hypercalciuria, absorptive, 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• idiopathic inherited hypercalciuria

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1954 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018417.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY10	NM_018417.6	MANE Select	c.3542A>G	p.Asn1181Ser	missense	Exon 25 of 33	NP_060887.2
	ADCY10	NM_001297772.2		c.3266A>G	p.Asn1089Ser	missense	Exon 25 of 33	NP_001284701.1
	ADCY10	NM_001167749.3		c.3083A>G	p.Asn1028Ser	missense	Exon 22 of 30	NP_001161221.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY10	ENST00000367851.9	TSL:1 MANE Select	c.3542A>G	p.Asn1181Ser	missense	Exon 25 of 33	ENSP00000356825.4
	ADCY10	ENST00000367848.1	TSL:1	c.3266A>G	p.Asn1089Ser	missense	Exon 25 of 33	ENSP00000356822.1
	ADCY10	ENST00000485964.5	TSL:5	n.*428A>G		non_coding_transcript_exon	Exon 6 of 15	ENSP00000476402.1

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

GnomAD2 exomes AF: 0.00383 AC: 963 AN: 251452 AF XY: 0.00276

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 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

African (AFR) AF: 0.0430 AC: 1438 AN: 33478

American (AMR) AF: 0.00454 AC: 203 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1111990

Other (OTH) AF: 0.00275 AC: 166 AN: 60396

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

African (AFR) AF: 0.0445 AC: 1849 AN: 41544

American (AMR) AF: 0.00524 AC: 80 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68014

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00480 Hom.: 21

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.52
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.022
Sift	Benign	0.45	T
Sift4G	Benign	0.36	T
Polyphen		0.0060	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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs116510137; hg19: chr1-167802276;