chr14-24322076-C-T

Variant names:

• chr14-24322076-C-T
• rs762502220
• NM_001198568.2:c.2576G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001198568.2(ADCY4):​c.2576G>A​(p.Arg859Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,612,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: ADCY4 NM_001198568.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32604867).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001198568.2. 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
	ADCY4	NM_001198568.2	MANE Select	c.2576G>A	p.Arg859Gln	missense	Exon 20 of 25	NP_001185497.1	Q8NFM4-1
	ADCY4	NM_001198592.2		c.2576G>A	p.Arg859Gln	missense	Exon 21 of 26	NP_001185521.1	Q8NFM4-1
	ADCY4	NM_139247.4		c.2576G>A	p.Arg859Gln	missense	Exon 21 of 26	NP_640340.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY4	ENST00000418030.7	TSL:1 MANE Select	c.2576G>A	p.Arg859Gln	missense	Exon 20 of 25	ENSP00000393177.2	Q8NFM4-1
	ADCY4	ENST00000554068.6	TSL:1	c.2576G>A	p.Arg859Gln	missense	Exon 21 of 26	ENSP00000452250.2	Q8NFM4-1
	ADCY4	ENST00000554781.5	TSL:1	n.*1258G>A		non_coding_transcript_exon	Exon 20 of 25	ENSP00000450477.1	G3V258

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 250440 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000466 AC: 68 AN: 1459914 Hom.: 0 Cov.: 34 AF XY: 0.0000399 AC XY: 29 AN XY: 726022

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.0000224 AC: 1 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1110506

Other (OTH) AF: 0.0000498 AC: 3 AN: 60292

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.34
Sift	Benign	0.16	T
Sift4G	Benign	0.32	T
Polyphen		0.93	P
Vest4		0.43
MutPred		0.47		Gain of catalytic residue at L864 (P = 0.0021)
MVP		0.92
MPC		1.2
ClinPred		0.62	D
GERP RS		5.3
Varity_R		0.14
gMVP		0.54
Mutation Taster		=87/13	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: rs762502220; hg19: chr14-24791282;