rs1042009

Variant names:

• chr7-45664372-G-A
• rs1042009
• NM_021116.4:c.1605+2158G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-45664372-G-A
• chr7-45664372-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021116.4(ADCY1):​c.1605+2158G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,535,732 control chromosomes in the GnomAD database, including 332,157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.55 (26095 hom., cov: 31)
  • Exomes 𝑓: 0.66 (306062 hom.)
• Consequence: ADCY1 NM_021116.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.337
• Publications: 15 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 7-45664372-G-A is Benign according to our data. Variant chr7-45664372-G-A is described in ClinVar as Benign. ClinVar VariationId is 1280820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADCY1	NM_021116.4	c.1605+2158G>A		intron_variant	Intron 8 of 19	ENST00000297323.12	NP_066939.1
ADCY1	NM_001281768.2	c.1014G>A	p.Thr338Thr	synonymous_variant	Exon 10 of 10		NP_001268697.1
ADCY1	XM_005249585.3	c.1689G>A	p.Thr563Thr	synonymous_variant	Exon 9 of 9		XP_005249642.1
ADCY1	XM_005249584.4	c.1605+2158G>A		intron_variant	Intron 8 of 18		XP_005249641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADCY1	ENST00000297323.12	c.1605+2158G>A		intron_variant	Intron 8 of 19	1	NM_021116.4	ENSP00000297323.7
ADCY1	ENST00000432715.5	c.1014G>A	p.Thr338Thr	synonymous_variant	Exon 10 of 10	2		ENSP00000392721.1
ADCY1	ENST00000621543.1	c.1014G>A	p.Thr338Thr	synonymous_variant	Exon 9 of 9	5		ENSP00000479770.1
ADCY1	ENST00000646653.1	n.546+2158G>A		intron_variant	Intron 4 of 7

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83044 AN: 151908 Hom.: 26089 Cov.: 31

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.559

GnomAD2 exomes AF: 0.631 AC: 86273 AN: 136700 AF XY: 0.642

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.651

Gnomad ASJ exome AF: 0.654

Gnomad EAS exome AF: 0.312

Gnomad FIN exome AF: 0.728

Gnomad NFE exome AF: 0.679

Gnomad OTH exome AF: 0.659

GnomAD4 exome AF: 0.659 AC: 911446 AN: 1383706 Hom.: 306062 Cov.: 53 AF XY: 0.662 AC XY: 452105 AN XY: 682780

African (AFR) AF: 0.206 AC: 6516 AN: 31594

American (AMR) AF: 0.646 AC: 23061 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 16586 AN: 25180

East Asian (EAS) AF: 0.375 AC: 13401 AN: 35726

South Asian (SAS) AF: 0.716 AC: 56762 AN: 79224

European-Finnish (FIN) AF: 0.730 AC: 24741 AN: 33896

Middle Eastern (MID) AF: 0.670 AC: 3805 AN: 5676

European-Non Finnish (NFE) AF: 0.677 AC: 729886 AN: 1078812

Other (OTH) AF: 0.634 AC: 36688 AN: 57900

GnomAD4 genome AF: 0.546 AC: 83077 AN: 152026 Hom.: 26095 Cov.: 31 AF XY: 0.552 AC XY: 41011 AN XY: 74306

African (AFR) AF: 0.228 AC: 9447 AN: 41452

American (AMR) AF: 0.638 AC: 9752 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2291 AN: 3468

East Asian (EAS) AF: 0.327 AC: 1691 AN: 5168

South Asian (SAS) AF: 0.701 AC: 3370 AN: 4804

European-Finnish (FIN) AF: 0.735 AC: 7782 AN: 10588

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.688 AC: 46723 AN: 67954

Other (OTH) AF: 0.554 AC: 1167 AN: 2106

Alfa AF: 0.630 Hom.: 117421

Bravo AF: 0.514

Asia WGS AF: 0.526 AC: 1826 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.42
PhyloP100		-0.34
Mutation Taster		=100/0	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: rs1042009; hg19: chr7-45703971; COSMIC: COSV52032848;