Genetic Variant NM_018417.6:c.4713G>T (chr1-167809798-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_018417.6(ADCY10):c.4713G>T(p.Trp1571Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADCY10
NM_018417.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.77

Publications

0 publications found

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
idiopathic inherited hypercalciuria
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ADCY10 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.806

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADCY10	NM_018417.6	MANE Select	c.4713G>T	p.Trp1571Cys	missense	Exon 33 of 33	NP_060887.2	Q96PN6-1
ADCY10	NM_001297772.2		c.4437G>T	p.Trp1479Cys	missense	Exon 33 of 33	NP_001284701.1	Q96PN6-2
ADCY10	NM_001167749.3		c.4254G>T	p.Trp1418Cys	missense	Exon 30 of 30	NP_001161221.1	Q96PN6-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADCY10	ENST00000367851.9	TSL:1 MANE Select	c.4713G>T	p.Trp1571Cys	missense	Exon 33 of 33	ENSP00000356825.4	Q96PN6-1
ADCY10	ENST00000367848.1	TSL:1	c.4437G>T	p.Trp1479Cys	missense	Exon 33 of 33	ENSP00000356822.1	Q96PN6-2
ADCY10	ENST00000485964.5	TSL:5	n.*1649G>T		non_coding_transcript_exon	Exon 15 of 15	ENSP00000476402.1	V9GY51

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

M_CAP

Benign

0.074

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.5

PhyloP100

3.8

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.69

MutPred

0.61

Gain of catalytic residue at L1572 (P = 0.0108)

MVP

0.61

MPC

0.69

ClinPred

0.99

GERP RS

5.5

Varity_R

0.58

gMVP

0.74

Mutation Taster

=69/31

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over