6-151305898-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.612

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=0.05098942).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP12	NM_005100.4	c.314C>T	p.Thr105Ile	missense_variant	3/5	ENST00000402676.7
AKAP12	XM_017011517.3	c.314C>T	p.Thr105Ile	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP12	ENST00000402676.7	c.314C>T	p.Thr105Ile	missense_variant	3/5	5	NM_005100.4	A2
AKAP12	ENST00000253332.5	c.314C>T	p.Thr105Ile	missense_variant	2/4	1		A2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152164 Hom.: 0 Cov.: 32

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: 25 AN: 239080 Hom.: 0 AF XY: 0.000116 AC XY: 15 AN XY: 129162

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.: 0 Cov.: 29 AF XY: 0.000145 AC XY: 105 AN XY: 723848

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: 26 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74330

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.: 0

Bravo AF: 0.000178

ExAC AF: 0.0000824 AC: 10

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 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	T
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	N
LIST_S2	Benign	0.39	T;.
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
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	D
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

Other links and lift over

dbSNP: rs61755980; hg19: chr6-151627033;