14-24322949-G-A

Position:

• chr14-24322949-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001198568.2(ADCY4):​c.2297C>T​(p.Ser766Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,460,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ADCY4 NM_001198568.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

Genes affected

ADCY4 (HGNC:235): (adenylate cyclase 4) This gene encodes a member of the family of adenylate cyclases, which are membrane-associated enzymes that catalyze the formation of the secondary messenger cyclic adenosine monophosphate (cAMP). Mouse studies show that adenylate cyclase 4, along with adenylate cyclases 2 and 3, is expressed in olfactory cilia, suggesting that several different adenylate cyclases may couple to olfactory receptors and that there may be multiple receptor-mediated mechanisms for the generation of cAMP signals. Alternative splicing results in transcript variants. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22745442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADCY4	NM_001198568.2	c.2297C>T	p.Ser766Leu	missense_variant	18/25	ENST00000418030.7
ADCY4	NM_001198592.2	c.2297C>T	p.Ser766Leu	missense_variant	19/26
ADCY4	NM_139247.4	c.2297C>T	p.Ser766Leu	missense_variant	19/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADCY4	ENST00000418030.7	c.2297C>T	p.Ser766Leu	missense_variant	18/25	1	NM_001198568.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460456 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 726416

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2022

The c.2297C>T (p.S766L) alteration is located in exon 18 (coding exon 18) of the ADCY4 gene. This alteration results from a C to T substitution at nucleotide position 2297, causing the serine (S) at amino acid position 766 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.0	L;L;L
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.89	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.71	T;T;T
Sift4G	Benign	0.68	T;T;T
Polyphen		0.0090	B;B;B
Vest4		0.39
MutPred		0.46		Gain of catalytic residue at A763 (P = 0);Gain of catalytic residue at A763 (P = 0);Gain of catalytic residue at A763 (P = 0);
MVP		0.89
MPC		0.54
ClinPred		0.52	D
GERP RS		4.0
Varity_R		0.085
gMVP		0.63

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: rs1323116643; hg19: chr14-24792155;