NM_015270.5:c.3291C>T

Variant names:

• chr12-48769027-G-A
• rs73296123
• NM_015270.5:c.3291C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015270.5(ADCY6):​c.3291C>T​(p.Ile1097Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,612,836 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (48 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (41 hom.)
• Consequence: ADCY6 NM_015270.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.301
• Publications: 0 publications found

Genes affected

ADCY6 (HGNC:237): (adenylate cyclase 6) This gene encodes a member of the adenylyl cyclase family of proteins, which are required for the synthesis of cyclic AMP. All members of this family have an intracellular N-terminus, a tandem repeat of six transmembrane domains separated by a cytoplasmic loop, and a C-terminal cytoplasmic domain. The two cytoplasmic regions bind ATP and form the catalytic core of the protein. Adenylyl cyclases are important effectors of transmembrane signaling pathways and are regulated by the activity of G protein coupled receptor signaling. This protein belongs to a small subclass of adenylyl cyclase proteins that are functionally related and are inhibited by protein kinase A, calcium ions and nitric oxide. A mutation in this gene is associated with arthrogryposis multiplex congenita. [provided by RefSeq, May 2015]

SPMIP11 (HGNC:48628): (sperm microtubule inner protein 11)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-48769027-G-A is Benign according to our data. Variant chr12-48769027-G-A is described in ClinVar as Benign. ClinVar VariationId is 788579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.301 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0134 (2035/152202) while in subpopulation AFR AF = 0.0459 (1905/41508). AF 95% confidence interval is 0.0442. There are 48 homozygotes in GnomAd4. There are 926 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015270.5. 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
	ADCY6	NM_015270.5	MANE Select	c.3291C>T	p.Ile1097Ile	synonymous	Exon 21 of 22	NP_056085.1	O43306-1
	ADCY6	NM_001390831.2		c.3291C>T	p.Ile1097Ile	synonymous	Exon 20 of 21	NP_001377760.1	O43306-1
	ADCY6	NM_001412819.1		c.3291C>T	p.Ile1097Ile	synonymous	Exon 21 of 22	NP_001399748.1	O43306-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADCY6	ENST00000357869.8	TSL:2 MANE Select	c.3291C>T	p.Ile1097Ile	synonymous	Exon 21 of 22	ENSP00000350536.4	O43306-1
	ADCY6	ENST00000307885.4	TSL:1	c.3291C>T	p.Ile1097Ile	synonymous	Exon 20 of 21	ENSP00000311405.4	O43306-1
	ADCY6	ENST00000960700.1		c.3372C>T	p.Ile1124Ile	synonymous	Exon 21 of 22	ENSP00000630759.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2033 AN: 152084 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00362 AC: 906 AN: 250180 AF XY: 0.00248

Gnomad AFR exome AF: 0.0498

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000873

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.00130 AC: 1906 AN: 1460634 Hom.: 41 Cov.: 32 AF XY: 0.00111 AC XY: 808 AN XY: 726598

African (AFR) AF: 0.0461 AC: 1544 AN: 33462

American (AMR) AF: 0.00293 AC: 131 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.000404 AC: 16 AN: 39640

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1111396

Other (OTH) AF: 0.00252 AC: 152 AN: 60316

GnomAD4 genome AF: 0.0134 AC: 2035 AN: 152202 Hom.: 48 Cov.: 32 AF XY: 0.0124 AC XY: 926 AN XY: 74410

African (AFR) AF: 0.0459 AC: 1905 AN: 41508

American (AMR) AF: 0.00608 AC: 93 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68008

Other (OTH) AF: 0.0104 AC: 22 AN: 2108

Alfa AF: 0.00578 Hom.: 18

Bravo AF: 0.0149

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.0000547

EpiControl AF: 0.000119

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	-0.45
CADD	Benign	7.7
DANN	Benign	0.84
PhyloP100		-0.30
Mutation Taster		=96/4	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: rs73296123; hg19: chr12-49162810;