chr7-45574777-C-G

Variant names:

• chr7-45574777-C-G
• rs74641956
• NM_021116.4:c.234C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021116.4(ADCY1):​c.234C>G​(p.Ala78Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,493,600 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 32)
  • Exomes 𝑓: 0.015 (212 hom.)
• Consequence: ADCY1 NM_021116.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.386
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 7-45574777-C-G is Benign according to our data. Variant chr7-45574777-C-G is described in ClinVar as Benign. ClinVar VariationId is 1238867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.386 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0149 (20040/1343204) while in subpopulation MID AF = 0.0369 (145/3930). AF 95% confidence interval is 0.032. There are 212 homozygotes in GnomAdExome4. There are 9681 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.234C>G	p.Ala78Ala	synonymous	Exon 1 of 20	NP_066939.1	Q08828
	ADCY1	NM_001281768.2		c.-330-112C>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.234C>G	p.Ala78Ala	synonymous	Exon 1 of 20	ENSP00000297323.7	Q08828
	ADCY1	ENST00000920696.1		c.234C>G	p.Ala78Ala	synonymous	Exon 1 of 19	ENSP00000590755.1
	ADCY1	ENST00000432715.5	TSL:2	c.-330-112C>G		intron	N/A	ENSP00000392721.1	C9J1J0

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1943 AN: 150290 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00278

Gnomad AMI AF: 0.0100

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0457

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00230

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.0461

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.0219

GnomAD2 exomes AF: 0.0153 AC: 1452 AN: 95198 AF XY: 0.0146

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00940

Gnomad ASJ exome AF: 0.0460

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0268

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0231

GnomAD4 exome AF: 0.0149 AC: 20040 AN: 1343204 Hom.: 212 Cov.: 31 AF XY: 0.0146 AC XY: 9681 AN XY: 662890

African (AFR) AF: 0.00368 AC: 100 AN: 27178

American (AMR) AF: 0.0104 AC: 274 AN: 26376

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 1045 AN: 22970

East Asian (EAS) AF: 0.0000322 AC: 1 AN: 31076

South Asian (SAS) AF: 0.00329 AC: 240 AN: 73020

European-Finnish (FIN) AF: 0.0256 AC: 1066 AN: 41672

Middle Eastern (MID) AF: 0.0369 AC: 145 AN: 3930

European-Non Finnish (NFE) AF: 0.0153 AC: 16223 AN: 1061448

Other (OTH) AF: 0.0170 AC: 946 AN: 55534

GnomAD4 genome AF: 0.0129 AC: 1943 AN: 150396 Hom.: 18 Cov.: 32 AF XY: 0.0132 AC XY: 969 AN XY: 73450

African (AFR) AF: 0.00277 AC: 114 AN: 41164

American (AMR) AF: 0.0144 AC: 219 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.0457 AC: 157 AN: 3436

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5026

South Asian (SAS) AF: 0.00230 AC: 11 AN: 4786

European-Finnish (FIN) AF: 0.0302 AC: 314 AN: 10406

Middle Eastern (MID) AF: 0.0490 AC: 14 AN: 286

European-Non Finnish (NFE) AF: 0.0158 AC: 1059 AN: 67148

Other (OTH) AF: 0.0217 AC: 45 AN: 2078

Alfa AF: 0.0106 Hom.: 7

Bravo AF: 0.0117

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.5
DANN	Benign	0.46
PhyloP100		0.39
PromoterAI		-0.029	Neutral
Mutation Taster		=100/0	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: rs74641956; hg19: chr7-45614376; COSMIC: COSV52040425; COSMIC: COSV52040425;