chr7-45574592-G-A

Position:

• chr7-45574592-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_021116.4(ADCY1):​c.49G>A​(p.Glu17Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000468 in 1,068,418 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: ADCY1 NM_021116.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

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
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADCY1. . Gene score misZ 4.3801 (greater than the threshold 3.09). Trascript score misZ 4.6991 (greater than threshold 3.09). GenCC has associacion of gene with hearing loss, autosomal recessive, autosomal recessive nonsyndromic hearing loss 44.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14397839).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY1	NM_021116.4	c.49G>A	p.Glu17Lys	missense_variant	1/20	ENST00000297323.12	NP_066939.1
ADCY1	XM_005249584.4	c.49G>A	p.Glu17Lys	missense_variant	1/19		XP_005249641.1
ADCY1	XM_005249585.3	c.49G>A	p.Glu17Lys	missense_variant	1/9		XP_005249642.1
ADCY1	NM_001281768.2	c.-330-297G>A		intron_variant			NP_001268697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY1	ENST00000297323.12	c.49G>A	p.Glu17Lys	missense_variant	1/20	1	NM_021116.4	ENSP00000297323	P1
ADCY1	ENST00000432715.5	c.-330-297G>A		intron_variant		2		ENSP00000392721

Frequencies

GnomAD3 genomes AF: 0.00000687 AC: 1 AN: 145502 Hom.: 0 Cov.: 31

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: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000433 AC: 4 AN: 922916 Hom.: 0 Cov.: 29 AF XY: 0.00000463 AC XY: 2 AN XY: 431858

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: 0.00000488

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000687 AC: 1 AN: 145502 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 1 AN XY: 70724

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000152

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 17 of the ADCY1 protein (p.Glu17Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ADCY1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.18
Sift	Benign	0.65	T
Sift4G	Benign	0.51	T
Polyphen		0.0020	B
Vest4		0.11
MutPred		0.25		Gain of MoRF binding (P = 0.0054);
MVP		0.47
MPC		1.4
ClinPred		0.23	T
GERP RS		3.2
Varity_R		0.042
gMVP		0.24

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: rs932221184; hg19: chr7-45614191;