6-151349152-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005100.4(AKAP12):c.761C>T(p.Pro254Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,613,718 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (79 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (56 hom.)
• Consequence: AKAP12 NM_005100.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.177

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019782484).
• BP6: Variant 6-151349152-C-T is Benign according to our data. Variant chr6-151349152-C-T is described in ClinVar as [Benign]. Clinvar id is 768115.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP12	NM_005100.4	c.761C>T	p.Pro254Leu	missense_variant	4/5	ENST00000402676.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP12	ENST00000402676.7	c.761C>T	p.Pro254Leu	missense_variant	4/5	5	NM_005100.4	A2

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2441 AN: 151942 Hom.: 79 Cov.: 31

Gnomad AFR AF: 0.0555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00702

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00435 AC: 1087 AN: 249772 Hom.: 25 AF XY: 0.00332 AC XY: 449 AN XY: 135380

Gnomad AFR exome AF: 0.0577

Gnomad AMR exome AF: 0.00354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00173 AC: 2533 AN: 1461658 Hom.: 56 Cov.: 74 AF XY: 0.00152 AC XY: 1104 AN XY: 727118

Gnomad4 AFR exome AF: 0.0571

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.00460

GnomAD4 genome AF: 0.0161 AC: 2445 AN: 152060 Hom.: 79 Cov.: 31 AF XY: 0.0161 AC XY: 1197 AN XY: 74316

Gnomad4 AFR AF: 0.0555

Gnomad4 AMR AF: 0.00688

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00292 Hom.: 15

Bravo AF: 0.0192

ESP6500AA AF: 0.0506 AC: 223

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00549 AC: 667

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.13
Dann	Benign	0.75
DEOGEN2	Benign	0.021	T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.76	T;.;T;T
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.90	N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.9	N;N;N;N
REVEL	Benign	0.020
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.97	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.062
MVP		0.10
MPC		0.17
ClinPred		0.00039	T
GERP RS		-2.0
Varity_R		0.022
gMVP		0.024

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: rs73780648; hg19: chr6-151670287;