7-45574643-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021116.4(ADCY1):​c.100C>T​(p.Arg34Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000018 in 1,110,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R34G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: ADCY1 NM_021116.4 missense
• Clinical Significance: Not reported in ClinVar
• 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, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39251262).

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>T	p.Arg34Trp	missense	Exon 1 of 20	NP_066939.1	Q08828
	ADCY1	NM_001281768.2		c.-330-246C>T		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>T	p.Arg34Trp	missense	Exon 1 of 20	ENSP00000297323.7	Q08828
	ADCY1	ENST00000920696.1		c.100C>T	p.Arg34Trp	missense	Exon 1 of 19	ENSP00000590755.1
	ADCY1	ENST00000432715.5	TSL:2	c.-330-246C>T		intron	N/A	ENSP00000392721.1	C9J1J0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000180 AC: 2 AN: 1110898 Hom.: 0 Cov.: 30 AF XY: 0.00000188 AC XY: 1 AN XY: 532032

African (AFR) AF: 0.00 AC: 0 AN: 22264

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 24778

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

European-Non Finnish (NFE) AF: 0.00000213 AC: 2 AN: 937144

Other (OTH) AF: 0.00 AC: 0 AN: 44116

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.24
Sift	Benign	0.063	T
Sift4G	Uncertain	0.028	D
Polyphen		0.95	P
Vest4		0.18
MutPred		0.56		Loss of disorder (P = 0.0118)
MVP		0.47
MPC		1.9
ClinPred		0.47	T
GERP RS		-0.38
PromoterAI		0.026	Neutral
Varity_R		0.099
gMVP		0.31
Mutation Taster		=98/2	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;