rs61729596

Variant names:

• chr7-45662163-C-T
• rs61729596
• NM_021116.4:c.1554C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_021116.4(ADCY1):​c.1554C>T​(p.Phe518Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.0208 in 1,613,988 control chromosomes in the GnomAD database, including 444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (31 hom., cov: 32)
  • Exomes 𝑓: 0.021 (413 hom.)
• Consequence: ADCY1 NM_021116.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.70
• Publications: 4 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 7-45662163-C-T is Benign according to our data. Variant chr7-45662163-C-T is described in ClinVar as Benign. ClinVar VariationId is 517531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0155 (2359/152284) while in subpopulation NFE AF = 0.0241 (1640/68030). AF 95% confidence interval is 0.0231. There are 31 homozygotes in GnomAd4. There are 1190 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR,Unknown gene

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.1554C>T	p.Phe518Phe	synonymous	Exon 8 of 20	NP_066939.1
	ADCY1	NM_001281768.2		c.879C>T	p.Phe293Phe	synonymous	Exon 9 of 10	NP_001268697.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY1	ENST00000297323.12	TSL:1 MANE Select	c.1554C>T	p.Phe518Phe	synonymous	Exon 8 of 20	ENSP00000297323.7
	ADCY1	ENST00000920696.1		c.1404C>T	p.Phe468Phe	synonymous	Exon 7 of 19	ENSP00000590755.1
	ADCY1	ENST00000432715.5	TSL:2	c.879C>T	p.Phe293Phe	synonymous	Exon 9 of 10	ENSP00000392721.1

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2362 AN: 152166 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0241

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0180 AC: 4523 AN: 251098 AF XY: 0.0192

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.00695

Gnomad ASJ exome AF: 0.00904

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.0234

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0213 AC: 31207 AN: 1461704 Hom.: 413 Cov.: 31 AF XY: 0.0217 AC XY: 15807 AN XY: 727152

African (AFR) AF: 0.00343 AC: 115 AN: 33480

American (AMR) AF: 0.00722 AC: 323 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00899 AC: 235 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0263 AC: 2268 AN: 86206

European-Finnish (FIN) AF: 0.0269 AC: 1437 AN: 53394

Middle Eastern (MID) AF: 0.0239 AC: 138 AN: 5768

European-Non Finnish (NFE) AF: 0.0230 AC: 25560 AN: 1111932

Other (OTH) AF: 0.0187 AC: 1130 AN: 60388

GnomAD4 genome AF: 0.0155 AC: 2359 AN: 152284 Hom.: 31 Cov.: 32 AF XY: 0.0160 AC XY: 1190 AN XY: 74454

African (AFR) AF: 0.00296 AC: 123 AN: 41554

American (AMR) AF: 0.00699 AC: 107 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4816

European-Finnish (FIN) AF: 0.0271 AC: 288 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0241 AC: 1640 AN: 68030

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0165 Hom.: 11

Bravo AF: 0.0130

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.0243

EpiControl AF: 0.0222

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.80
PhyloP100		3.7
Mutation Taster		=96/4	polymorphism (auto)

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: rs61729596; hg19: chr7-45701762;