6-151348740-A-G

Position:

• chr6-151348740-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005100.4(AKAP12):​c.349A>G​(p.Lys117Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 1,590,998 control chromosomes in the GnomAD database, including 474,860 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.76 (42023 hom., cov: 21)
  • Exomes 𝑓: 0.78 (432837 hom.)
• Consequence: AKAP12 NM_005100.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.442

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]

AKAP12 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.87914E-7).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP12	NM_005100.4	c.349A>G	p.Lys117Glu	missense_variant	4/5	ENST00000402676.7	NP_005091.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP12	ENST00000402676.7	c.349A>G	p.Lys117Glu	missense_variant	4/5	5	NM_005100.4	ENSP00000384537.2

Frequencies

GnomAD3 genomes AF: 0.759 AC: 110917 AN: 146178 Hom.: 41997 Cov.: 21

Gnomad AFR AF: 0.714

Gnomad AMI AF: 0.631

Gnomad AMR AF: 0.809

Gnomad ASJ AF: 0.822

Gnomad EAS AF: 0.622

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.801

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.777

GnomAD3 exomes AF: 0.754 AC: 186973 AN: 248104 Hom.: 71091 AF XY: 0.748 AC XY: 100370 AN XY: 134180

Gnomad AFR exome AF: 0.705

Gnomad AMR exome AF: 0.828

Gnomad ASJ exome AF: 0.825

Gnomad EAS exome AF: 0.595

Gnomad SAS exome AF: 0.658

Gnomad FIN exome AF: 0.787

Gnomad NFE exome AF: 0.775

Gnomad OTH exome AF: 0.781

GnomAD4 exome AF: 0.776 AC: 1121038 AN: 1444722 Hom.: 432837 Cov.: 33 AF XY: 0.772 AC XY: 555037 AN XY: 718520

Gnomad4 AFR exome AF: 0.716

Gnomad4 AMR exome AF: 0.827

Gnomad4 ASJ exome AF: 0.834

Gnomad4 EAS exome AF: 0.700

Gnomad4 SAS exome AF: 0.657

Gnomad4 FIN exome AF: 0.797

Gnomad4 NFE exome AF: 0.785

Gnomad4 OTH exome AF: 0.775

GnomAD4 genome AF: 0.759 AC: 110995 AN: 146276 Hom.: 42023 Cov.: 21 AF XY: 0.760 AC XY: 53938 AN XY: 70958

Gnomad4 AFR AF: 0.715

Gnomad4 AMR AF: 0.809

Gnomad4 ASJ AF: 0.822

Gnomad4 EAS AF: 0.622

Gnomad4 SAS AF: 0.659

Gnomad4 FIN AF: 0.801

Gnomad4 NFE AF: 0.782

Gnomad4 OTH AF: 0.778

Alfa AF: 0.772 Hom.: 85662

Bravo AF: 0.752

TwinsUK AF: 0.780 AC: 2894

ALSPAC AF: 0.773 AC: 2981

ESP6500AA AF: 0.698 AC: 3076

ESP6500EA AF: 0.787 AC: 6767

ExAC AF: 0.747 AC: 90652

Asia WGS AF: 0.647 AC: 2249 AN: 3476

EpiCase AF: 0.780

EpiControl AF: 0.783

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.7
DANN	Benign	0.60
DEOGEN2	Benign	0.012	T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.16	T;.;T;T
MetaRNN	Benign	7.9e-7	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.46	N;N;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.2	N;N;N;N
REVEL	Benign	0.042
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.015
MPC		0.23
ClinPred		0.0015	T
GERP RS		2.8
Varity_R		0.032
gMVP		0.015

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: rs10872670; hg19: chr6-151669875; COSMIC: COSV53577250;