1-167856368-A-T

Variant names:

• chr1-167856368-A-T
• rs2071922
• NM_018417.6:c.1968T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018417.6(ADCY10):​c.1968T>A​(p.Phe656Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F656F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADCY10 NM_018417.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700
• Publications: 12 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY10	NM_018417.6	MANE Select	c.1968T>A	p.Phe656Leu	missense	Exon 17 of 33	NP_060887.2
	ADCY10	NM_001297772.2		c.1692T>A	p.Phe564Leu	missense	Exon 17 of 33	NP_001284701.1
	ADCY10	NM_001167749.3		c.1509T>A	p.Phe503Leu	missense	Exon 14 of 30	NP_001161221.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY10	ENST00000367851.9	TSL:1 MANE Select	c.1968T>A	p.Phe656Leu	missense	Exon 17 of 33	ENSP00000356825.4
	ADCY10	ENST00000367848.1	TSL:1	c.1692T>A	p.Phe564Leu	missense	Exon 17 of 33	ENSP00000356822.1
	ADCY10	ENST00000545172.5	TSL:2	c.1509T>A	p.Phe503Leu	missense	Exon 14 of 30	ENSP00000441992.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.0070
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.38
Sift	Benign	0.057	T
Sift4G	Benign	0.17	T
Polyphen		0.82	P
Vest4		0.64
MutPred		0.49		Gain of ubiquitination at K659 (P = 0.143)
MVP		0.20
MPC		0.48
ClinPred		0.97	D
GERP RS		-7.4
Varity_R		0.27
gMVP		0.32
Mutation Taster		=100/0	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: rs2071922; hg19: chr1-167825606;