NM_020546.3:c.136C>T

Variant names:

• chr5-7396432-C-T
• NM_020546.3:c.136C>T

Variant summary

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

The NM_020546.3(ADCY2):​c.136C>T​(p.Leu46Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,428,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ADCY2 NM_020546.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.87
• Publications: 0 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 2 ACMG points.

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

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.136C>T	p.Leu46Phe	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.136C>T	p.Leu46Phe	missense	Exon 1 of 25	ENSP00000342952.4	Q08462-1
	ADCY2	ENST00000915366.1		c.136C>T	p.Leu46Phe	missense	Exon 1 of 25	ENSP00000585425.1
	ADCY2	ENST00000915369.1		c.136C>T	p.Leu46Phe	missense	Exon 1 of 24	ENSP00000585428.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000210 AC: 3 AN: 1428752 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 710668

African (AFR) AF: 0.00 AC: 0 AN: 30546

American (AMR) AF: 0.0000242 AC: 1 AN: 41328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 36202

South Asian (SAS) AF: 0.00 AC: 0 AN: 83410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1095918

Other (OTH) AF: 0.00 AC: 0 AN: 58766

GnomAD4 genome Cov.: 31

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	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.38
Sift	Benign	0.033	D
Sift4G	Uncertain	0.048	D
Polyphen		0.19	B
Vest4		0.42
MutPred		0.46		Loss of catalytic residue at L46 (P = 0.1431)
MVP		0.74
MPC		0.91
ClinPred		0.84	D
GERP RS		2.6
PromoterAI		0.033	Neutral
Varity_R		0.26
gMVP		0.70
Mutation Taster		=68/32	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

hg19: chr5-7396545;