Variant 6-151305898-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005100.4(AKAP12):c.314C>T(p.Thr105Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,608,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

AKAP12
NM_005100.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.612

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.05098942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP12	NM_005100.4 link	c.314C>T	p.Thr105Ile	missense_variant	3/5	ENST00000402676.7	NP_005091.2	Q02952-1Q86TJ9
AKAP12	XM_017011517.3 link	c.314C>T	p.Thr105Ile	missense_variant	3/5		XP_016867006.1	Q02952-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP12	ENST00000402676.7 link	c.314C>T	p.Thr105Ile	missense_variant	3/5	5	NM_005100.4	ENSP00000384537.2		Q02952-1
AKAP12	ENST00000253332.5 link	c.314C>T	p.Thr105Ile	missense_variant	2/4	1		ENSP00000253332.1		Q02952-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000105

AC:

AN:

239080

Hom.:

AF XY:

0.000116

AC XY:

AN XY:

129162

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000908

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000342

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.000141

AC:

206

AN:

1456124

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

105

AN XY:

723848

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.000115

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000173

Gnomad4 OTH exome

AF:

0.0000996

GnomAD4 genome

AF:

0.000171

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000213

Hom.:

Bravo

AF:

0.000178

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The c.314C>T (p.T105I) alteration is located in exon 3 (coding exon 2) of the AKAP12 gene. This alteration results from a C to T substitution at nucleotide position 314, causing the threonine (T) at amino acid position 105 to be replaced by an isoleucine (I). 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

0.22

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.9

DANN

Benign

0.64

DEOGEN2

Benign

0.25

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.39

T;.

M_CAP

Benign

0.0068

MetaRNN

Benign

0.051

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.020

Sift

Benign

0.11

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.034

B;B

Vest4

0.089

MVP

0.39

MPC

0.18

ClinPred

0.95

GERP RS

1.6

Varity_R

0.043

gMVP

0.033

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over