NM_021116.4:c.59G>A

Variant names:

• chr7-45574602-G-A
• rs1050576340
• NM_021116.4:c.59G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021116.4(ADCY1):​c.59G>A​(p.Gly20Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 969,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ADCY1 NM_021116.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.70

Genes affected

ADCY1 (HGNC:232): (adenylate cyclase 1) This gene encodes a member of the of adenylate cyclase gene family that is primarily expressed in the brain. This protein is regulated by calcium/calmodulin concentration and may be involved in brain development. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26410916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY1	NM_021116.4	c.59G>A	p.Gly20Asp	missense_variant	Exon 1 of 20	ENST00000297323.12	NP_066939.1
ADCY1	XM_005249584.4	c.59G>A	p.Gly20Asp	missense_variant	Exon 1 of 19		XP_005249641.1
ADCY1	XM_005249585.3	c.59G>A	p.Gly20Asp	missense_variant	Exon 1 of 9		XP_005249642.1
ADCY1	NM_001281768.2	c.-330-287G>A		intron_variant	Intron 1 of 9		NP_001268697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY1	ENST00000297323.12	c.59G>A	p.Gly20Asp	missense_variant	Exon 1 of 20	1	NM_021116.4	ENSP00000297323.7
ADCY1	ENST00000432715.5	c.-330-287G>A		intron_variant	Intron 1 of 9	2		ENSP00000392721.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000134 AC: 13 AN: 969352 Hom.: 0 Cov.: 29 AF XY: 0.0000176 AC XY: 8 AN XY: 455346

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.20
Sift	Benign	0.064	T
Sift4G	Benign	0.097	T
Polyphen		0.0020	B
Vest4		0.27
MutPred		0.22		Loss of methylation at R23 (P = 0.0508);
MVP		0.63
MPC		1.6
ClinPred		0.10	T
GERP RS		2.0
Varity_R		0.084
gMVP		0.32

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: rs1050576340; hg19: chr7-45614201;