12-48771867-C-T

Position:

• chr12-48771867-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 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

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ADCY6. . Gene score misZ 2.6826 (greater than the threshold 3.09). Trascript score misZ 3.621 (greater than threshold 3.09). GenCC has associacion of gene with lethal congenital contracture syndrome 8, hypomyelination neuropathy-arthrogryposis syndrome.
• 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 id is 3039504.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADCY6	NM_015270.5	c.2894G>A	p.Arg965His	missense_variant	19/22	ENST00000357869.8	NP_056085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADCY6	ENST00000357869.8	c.2894G>A	p.Arg965His	missense_variant	19/22	2	NM_015270.5	ENSP00000350536	P1

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

GnomAD3 exomes AF: 0.00123 AC: 310 AN: 251480 Hom.: 1 AF XY: 0.00127 AC XY: 172 AN XY: 135918

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00318

Gnomad4 OTH exome AF: 0.00280

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

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00192 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

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ADCY6-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 26, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;.;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.4	.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.082	T;T;D
Sift4G	Benign	0.085	T;T;T
Polyphen		0.51	P;P;B
Vest4		0.47
MVP		0.69
MPC		1.4
ClinPred		0.089	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs143958339; hg19: chr12-49165650;