rs1457078080

Variant names:

• chr5-7396486-G-T
• rs1457078080
• NM_020546.3:c.190G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-7396486-G-T
• chr5-7396486-G-A

Variant summary

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

The NM_020546.3(ADCY2):​c.190G>T​(p.Val64Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000128 in 1,566,616 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V64L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ADCY2 NM_020546.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.07
• Publications: 2 publications found

Genes affected

ADCY2 (HGNC:233): (adenylate cyclase 2) 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). This enzyme is insensitive to Ca(2+)/calmodulin, and is stimulated by the G protein beta and gamma subunit complex. [provided by RefSeq, Jul 2008]

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=0.34081352).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020546.3. 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
	ADCY2	NM_020546.3	MANE Select	c.190G>T	p.Val64Phe	missense	Exon 1 of 25	NP_065433.2	Q08462-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY2	ENST00000338316.9	TSL:1 MANE Select	c.190G>T	p.Val64Phe	missense	Exon 1 of 25	ENSP00000342952.4	Q08462-1
	ADCY2	ENST00000915366.1		c.190G>T	p.Val64Phe	missense	Exon 1 of 25	ENSP00000585425.1
	ADCY2	ENST00000915369.1		c.190G>T	p.Val64Phe	missense	Exon 1 of 24	ENSP00000585428.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151284 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1415332 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703916

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29400

American (AMR) AF: 0.00 AC: 0 AN: 40164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24628

East Asian (EAS) AF: 0.00 AC: 0 AN: 34322

South Asian (SAS) AF: 0.00 AC: 0 AN: 82606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5386

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089320

Other (OTH) AF: 0.00 AC: 0 AN: 58002

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151284 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73872

African (AFR) AF: 0.0000242 AC: 1 AN: 41316

American (AMR) AF: 0.00 AC: 0 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67772

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.26
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.18	T
Polyphen		0.037	B
Vest4		0.43
MutPred		0.45		Loss of stability (P = 0.1565)
MVP		0.86
MPC		1.0
ClinPred		0.91	D
GERP RS		2.8
PromoterAI		0.0088	Neutral
Varity_R		0.26
gMVP		0.91
Mutation Taster		=47/53	disease causing

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: rs1457078080; hg19: chr5-7396599;