rs41270737

Positions:

• chr1-167818241-T-C

Variant summary

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

The ENST00000367851.9(ADCY10):​c.4313A>G​(p.Asn1438Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0099 in 1,614,074 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (5 hom., cov: 33)
  • Exomes 𝑓: 0.010 (107 hom.)
• Consequence: ADCY10 ENST00000367851.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.592

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=0.004826337).
• BP6: Variant 1-167818241-T-C is Benign according to our data. Variant chr1-167818241-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 769248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00814 (1239/152296) while in subpopulation NFE AF= 0.0122 (832/68010). AF 95% confidence interval is 0.0115. There are 5 homozygotes in gnomad4. There are 581 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1239 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY10	NM_018417.6	c.4313A>G	p.Asn1438Ser	missense_variant	31/33	ENST00000367851.9	NP_060887.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY10	ENST00000367851.9	c.4313A>G	p.Asn1438Ser	missense_variant	31/33	1	NM_018417.6	ENSP00000356825	P1
ADCY10	ENST00000367848.1	c.4037A>G	p.Asn1346Ser	missense_variant	31/33	1		ENSP00000356822
ADCY10	ENST00000545172.5	c.3854A>G	p.Asn1285Ser	missense_variant	28/30	2		ENSP00000441992
ADCY10	ENST00000485964.5	c.*1249A>G		3_prime_UTR_variant, NMD_transcript_variant	13/15	5		ENSP00000476402

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 1238 AN: 152178 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0122

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00814 AC: 2048 AN: 251454 Hom.: 13 AF XY: 0.00849 AC XY: 1154 AN XY: 135900

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00676

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00679

Gnomad FIN exome AF: 0.00698

Gnomad NFE exome AF: 0.0110

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0101 AC: 14743 AN: 1461778 Hom.: 107 Cov.: 31 AF XY: 0.0100 AC XY: 7287 AN XY: 727192

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00736

Gnomad4 ASJ exome AF: 0.00957

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00691

Gnomad4 FIN exome AF: 0.00724

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00979

GnomAD4 genome AF: 0.00814 AC: 1239 AN: 152296 Hom.: 5 Cov.: 33 AF XY: 0.00780 AC XY: 581 AN XY: 74472

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.00631

Gnomad4 NFE AF: 0.0122

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.0100 Hom.: 12

Bravo AF: 0.00778

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0137 AC: 118

ExAC AF: 0.00822 AC: 998

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0118

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.79
DANN	Benign	0.67
DEOGEN2	Benign	0.054	.;T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.65	T;T;T
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	.;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.25	N;N;N
REVEL	Benign	0.055
Sift	Benign	0.81	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0060, 0.018	.;B;B
Vest4		0.26
MVP		0.46
MPC		0.090
ClinPred		0.0095	T
GERP RS		0.51
Varity_R		0.035
gMVP		0.075

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs41270737; hg19: chr1-167787479; COSMIC: COSV99057548; COSMIC: COSV99057548;