7-45574791-C-G

Variant names:

• chr7-45574791-C-G
• rs375141353
• NM_021116.4:c.248C>G

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.248C>G​(p.Ala83Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,395,046 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A83V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADCY1 NM_021116.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.678
• 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=0.17148185).

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.248C>G	p.Ala83Gly	missense	Exon 1 of 20	NP_066939.1	Q08828
	ADCY1	NM_001281768.2		c.-330-98C>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.248C>G	p.Ala83Gly	missense	Exon 1 of 20	ENSP00000297323.7	Q08828
	ADCY1	ENST00000920696.1		c.248C>G	p.Ala83Gly	missense	Exon 1 of 19	ENSP00000590755.1
	ADCY1	ENST00000432715.5	TSL:2	c.-330-98C>G		intron	N/A	ENSP00000392721.1	C9J1J0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1395046 Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2 AN XY: 691058

African (AFR) AF: 0.00 AC: 0 AN: 28892

American (AMR) AF: 0.00 AC: 0 AN: 35794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24322

East Asian (EAS) AF: 0.00 AC: 0 AN: 34268

South Asian (SAS) AF: 0.00 AC: 0 AN: 79102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4098

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1085536

Other (OTH) AF: 0.00 AC: 0 AN: 57588

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.85
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.68
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.15
Sift	Benign	0.37	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.56		Gain of disorder (P = 0.0737)
MVP		0.54
MPC		1.3
ClinPred		0.21	T
GERP RS		0.51
PromoterAI		0.083	Neutral
Varity_R		0.041
gMVP		0.24
Mutation Taster		=89/11	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: rs375141353; hg19: chr7-45614390;