6-151305841-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005100.4(AKAP12):c.257G>A(p.Gly86Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: AKAP12 NM_005100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.365

Genes affected

AKAP12 (HGNC:370): (A-kinase anchoring protein 12) The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is expressed in endothelial cells, cultured fibroblasts, and osteosarcoma cells. It associates with protein kinases A and C and phosphatase, and serves as a scaffold protein in signal transduction. This protein and RII PKA colocalize at the cell periphery. This protein is a cell growth-related protein. Antibodies to this protein can be produced by patients with myasthenia gravis. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053006053).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP12	NM_005100.4	c.257G>A	p.Gly86Glu	missense_variant	3/5	ENST00000402676.7
AKAP12	XM_017011517.3	c.257G>A	p.Gly86Glu	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP12	ENST00000402676.7	c.257G>A	p.Gly86Glu	missense_variant	3/5	5	NM_005100.4	A2
AKAP12	ENST00000253332.5	c.257G>A	p.Gly86Glu	missense_variant	2/4	1		A2

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250992 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461752 Hom.: 0 Cov.: 30 AF XY: 0.0000165 AC XY: 12 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74428

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

The c.257G>A (p.G86E) alteration is located in exon 3 (coding exon 2) of the AKAP12 gene. This alteration results from a G to A substitution at nucleotide position 257, causing the glycine (G) at amino acid position 86 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	3.9
Dann	Uncertain	0.99
DEOGEN2	Benign	0.019	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.56	T;.
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.81	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.15	N;N
REVEL	Benign	0.068
Sift	Uncertain	0.016	D;D
Sift4G	Benign	0.17	T;T
Polyphen		0.99	D;D
Vest4		0.30
MutPred		0.19		Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);
MVP		0.55
MPC		0.74
ClinPred		0.097	T
GERP RS		0.16
Varity_R		0.14
gMVP		0.036

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: rs534033209; hg19: chr6-151626976;