NM_021116.4:c.2454+5328C>T

Variant names:

• chr7-45692001-C-T
• rs11766222
• NM_021116.4:c.2454+5328C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021116.4(ADCY1):​c.2454+5328C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 152,056 control chromosomes in the GnomAD database, including 14,058 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (14058 hom., cov: 33)
• Consequence: ADCY1 NM_021116.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.339
• Publications: 5 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal recessive nonsyndromic hearing loss 44

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY1	NM_021116.4	c.2454+5328C>T		intron_variant	Intron 14 of 19	ENST00000297323.12	NP_066939.1
ADCY1	XM_005249584.4	c.2454+5328C>T		intron_variant	Intron 14 of 18		XP_005249641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY1	ENST00000297323.12	c.2454+5328C>T		intron_variant	Intron 14 of 19	1	NM_021116.4	ENSP00000297323.7

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63309 AN: 151936 Hom.: 14034 Cov.: 33

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.396

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.417 AC: 63382 AN: 152056 Hom.: 14058 Cov.: 33 AF XY: 0.411 AC XY: 30536 AN XY: 74318

African (AFR) AF: 0.545 AC: 22620 AN: 41476

American (AMR) AF: 0.318 AC: 4855 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1389 AN: 3472

East Asian (EAS) AF: 0.211 AC: 1089 AN: 5170

South Asian (SAS) AF: 0.210 AC: 1009 AN: 4814

European-Finnish (FIN) AF: 0.399 AC: 4208 AN: 10550

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26937 AN: 67986

Other (OTH) AF: 0.401 AC: 846 AN: 2112

Alfa AF: 0.428 Hom.: 3262

Bravo AF: 0.419

Asia WGS AF: 0.229 AC: 802 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.7
DANN	Benign	0.83
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11766222; hg19: chr7-45731600;