7-45574592-G-A

Variant names:

• chr7-45574592-G-A
• rs932221184
• NM_021116.4:c.49G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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. 15/22 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
• Publications: 0 publications found

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]

ADCY1 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 44

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14397839).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021116.4. 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
	ADCY1	NM_021116.4	MANE Select	c.49G>A	p.Glu17Lys	missense	Exon 1 of 20	NP_066939.1	Q08828
	ADCY1	NM_001281768.2		c.-330-297G>A		intron	N/A	NP_001268697.1	C9J1J0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY1	ENST00000297323.12	TSL:1 MANE Select	c.49G>A	p.Glu17Lys	missense	Exon 1 of 20	ENSP00000297323.7	Q08828
	ADCY1	ENST00000920696.1		c.49G>A	p.Glu17Lys	missense	Exon 1 of 19	ENSP00000590755.1
	ADCY1	ENST00000432715.5	TSL:2	c.-330-297G>A		intron	N/A	ENSP00000392721.1	C9J1J0

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

African (AFR) AF: 0.00 AC: 0 AN: 17986

American (AMR) AF: 0.00 AC: 0 AN: 3578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7996

East Asian (EAS) AF: 0.00 AC: 0 AN: 11088

South Asian (SAS) AF: 0.00 AC: 0 AN: 18060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2106

European-Non Finnish (NFE) AF: 0.00000488 AC: 4 AN: 819872

Other (OTH) AF: 0.00 AC: 0 AN: 32880

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

African (AFR) AF: 0.00 AC: 0 AN: 40524

American (AMR) AF: 0.00 AC: 0 AN: 14720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 4950

South Asian (SAS) AF: 0.00 AC: 0 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65632

Other (OTH) AF: 0.00 AC: 0 AN: 2012

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.2
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
PromoterAI		-0.0070	Neutral
Varity_R		0.042
gMVP		0.24
Mutation Taster		=97/3	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: rs932221184; hg19: chr7-45614191;