chr7-45574643-C-G

Variant names:

• chr7-45574643-C-G
• rs760606743
• NM_021116.4:c.100C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_021116.4(ADCY1):​c.100C>G​(p.Arg34Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000602 in 1,260,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: ADCY1 NM_021116.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.73
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038677454).

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.100C>G	p.Arg34Gly	missense	Exon 1 of 20	NP_066939.1	Q08828
	ADCY1	NM_001281768.2		c.-330-246C>G		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.100C>G	p.Arg34Gly	missense	Exon 1 of 20	ENSP00000297323.7	Q08828
	ADCY1	ENST00000920696.1		c.100C>G	p.Arg34Gly	missense	Exon 1 of 19	ENSP00000590755.1
	ADCY1	ENST00000432715.5	TSL:2	c.-330-246C>G		intron	N/A	ENSP00000392721.1	C9J1J0

Frequencies

GnomAD3 genomes AF: 0.000275 AC: 41 AN: 149326 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000974

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: 0.000317

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000491

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.000695 AC: 6 AN: 8636 AF XY: 0.000540

Gnomad AFR exome AF: 0.00781

Gnomad AMR exome AF: 0.00115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000646 AC: 718 AN: 1110898 Hom.: 0 Cov.: 30 AF XY: 0.000626 AC XY: 333 AN XY: 532032

African (AFR) AF: 0.000180 AC: 4 AN: 22264

American (AMR) AF: 0.000116 AC: 1 AN: 8608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14384

East Asian (EAS) AF: 0.00 AC: 0 AN: 24388

South Asian (SAS) AF: 0.00 AC: 0 AN: 32256

European-Finnish (FIN) AF: 0.000121 AC: 3 AN: 24778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2960

European-Non Finnish (NFE) AF: 0.000743 AC: 696 AN: 937144

Other (OTH) AF: 0.000317 AC: 14 AN: 44116

GnomAD4 genome AF: 0.000274 AC: 41 AN: 149428 Hom.: 0 Cov.: 32 AF XY: 0.000206 AC XY: 15 AN XY: 72938

African (AFR) AF: 0.0000972 AC: 4 AN: 41172

American (AMR) AF: 0.00 AC: 0 AN: 15034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5068

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000317 AC: 3 AN: 9456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000491 AC: 33 AN: 67156

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000332

ExAC AF: 0.0000820 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.24
Sift	Benign	0.39	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.45		Loss of MoRF binding (P = 0.0092)
MVP		0.37
MPC		1.6
ClinPred		0.012	T
GERP RS		-0.38
PromoterAI		0.0048	Neutral
Varity_R		0.14
gMVP		0.23
Mutation Taster		=95/5	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: rs760606743; hg19: chr7-45614242;