chr12-48770699-G-T

Variant names:

• chr12-48770699-G-T
• rs78519542
• NM_015270.5:c.3256+67C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015270.5(ADCY6):​c.3256+67C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,364,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ADCY6 NM_015270.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.732
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).

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.3256+67C>A		intron	N/A	NP_056085.1	O43306-1
	ADCY6	NM_001390831.2		c.3256+67C>A		intron	N/A	NP_001377760.1	O43306-1
	ADCY6	NM_001412819.1		c.3256+67C>A		intron	N/A	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.3256+67C>A		intron	N/A	ENSP00000350536.4	O43306-1
	ADCY6	ENST00000307885.4	TSL:1	c.3256+67C>A		intron	N/A	ENSP00000311405.4	O43306-1
	ADCY6	ENST00000960700.1		c.3337+67C>A		intron	N/A	ENSP00000630759.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1364804 Hom.: 0 AF XY: 0.00000294 AC XY: 2 AN XY: 681044

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31450

American (AMR) AF: 0.00 AC: 0 AN: 44308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 39006

South Asian (SAS) AF: 0.00 AC: 0 AN: 82922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4070

European-Non Finnish (NFE) AF: 0.00000194 AC: 2 AN: 1029086

Other (OTH) AF: 0.00 AC: 0 AN: 56986

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.6
DANN	Benign	0.87
PhyloP100		-0.73

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: rs78519542; hg19: chr12-49164482;