12-48771867-C-T

Variant names:

• chr12-48771867-C-T
• rs143958339
• NM_015270.5:c.2894G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_015270.5(ADCY6):​c.2894G>A​(p.Arg965His) variant causes a missense change. The variant allele was found at a frequency of 0.00252 in 1,614,160 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (12 hom.)
• Consequence: ADCY6 NM_015270.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.89
• Publications: 4 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]

MIR4701 (HGNC:41627): (microRNA 4701) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023034751).
• BP6: Variant 12-48771867-C-T is Benign according to our data. Variant chr12-48771867-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3039504.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.2894G>A	p.Arg965His	missense	Exon 19 of 22	NP_056085.1	O43306-1
	ADCY6	NM_001390831.2		c.2894G>A	p.Arg965His	missense	Exon 18 of 21	NP_001377760.1	O43306-1
	ADCY6	NM_001412819.1		c.2894G>A	p.Arg965His	missense	Exon 19 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.2894G>A	p.Arg965His	missense	Exon 19 of 22	ENSP00000350536.4	O43306-1
	ADCY6	ENST00000307885.4	TSL:1	c.2894G>A	p.Arg965His	missense	Exon 18 of 21	ENSP00000311405.4	O43306-1
	ADCY6	ENST00000960700.1		c.2975G>A	p.Arg992His	missense	Exon 19 of 22	ENSP00000630759.1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00123 AC: 310 AN: 251480 AF XY: 0.00127

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00261 AC: 3813 AN: 1461868 Hom.: 12 Cov.: 31 AF XY: 0.00253 AC XY: 1843 AN XY: 727236

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00152 AC: 68 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00318 AC: 3535 AN: 1112012

Other (OTH) AF: 0.00280 AC: 169 AN: 60396

GnomAD4 genome AF: 0.00164 AC: 249 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00167 AC XY: 124 AN XY: 74454

African (AFR) AF: 0.000650 AC: 27 AN: 41558

American (AMR) AF: 0.00360 AC: 55 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00240 AC: 163 AN: 68022

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00166

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.000997 AC: 121

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00249

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	ADCY6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.34
Sift	Benign	0.082	T
Sift4G	Benign	0.085	T
Polyphen		0.51	P
Vest4		0.47
MVP		0.69
MPC		1.4
ClinPred		0.089	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.62
Mutation Taster		=86/14	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: rs143958339; hg19: chr12-49165650;