chr6-151348777-C-T

Variant names:

• chr6-151348777-C-T
• rs1275973826
• NM_005100.4:c.386C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005100.4(AKAP12):​c.386C>T​(p.Ala129Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000819 in 1,464,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: AKAP12 NM_005100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0570
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037814528).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005100.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP12	NM_005100.4	MANE Select	c.386C>T	p.Ala129Val	missense	Exon 4 of 5	NP_005091.2
	AKAP12	NM_144497.2		c.92C>T	p.Ala31Val	missense	Exon 2 of 3	NP_653080.1	Q02952-2
	AKAP12	NM_001370346.1		c.71C>T	p.Ala24Val	missense	Exon 2 of 3	NP_001357275.1	Q02952-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP12	ENST00000402676.7	TSL:5 MANE Select	c.386C>T	p.Ala129Val	missense	Exon 4 of 5	ENSP00000384537.2	Q02952-1
	AKAP12	ENST00000253332.5	TSL:1	c.386C>T	p.Ala129Val	missense	Exon 3 of 4	ENSP00000253332.1	Q02952-1
	AKAP12	ENST00000354675.10	TSL:1	c.92C>T	p.Ala31Val	missense	Exon 2 of 3	ENSP00000346702.6	Q02952-2

Frequencies

GnomAD3 genomes AF: 0.0000147 AC: 2 AN: 136312 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000304

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251342 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 10 AN: 1328242 Hom.: 0 Cov.: 54 AF XY: 0.00000910 AC XY: 6 AN XY: 659218

African (AFR) AF: 0.0000338 AC: 1 AN: 29602

American (AMR) AF: 0.0000247 AC: 1 AN: 40462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21208

East Asian (EAS) AF: 0.00 AC: 0 AN: 27766

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5046

European-Non Finnish (NFE) AF: 0.00000683 AC: 7 AN: 1024656

Other (OTH) AF: 0.00 AC: 0 AN: 51476

GnomAD4 genome AF: 0.0000147 AC: 2 AN: 136312 Hom.: 0 Cov.: 30 AF XY: 0.0000155 AC XY: 1 AN XY: 64700

African (AFR) AF: 0.00 AC: 0 AN: 36454

American (AMR) AF: 0.00 AC: 0 AN: 11598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 4390

South Asian (SAS) AF: 0.00 AC: 0 AN: 4248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000304 AC: 2 AN: 65692

Other (OTH) AF: 0.00 AC: 0 AN: 1856

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.3
DANN	Benign	0.94
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.26	N
PhyloP100		0.057
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.027
Sift	Benign	0.44	T
Sift4G	Benign	0.91	T
Polyphen		0.070	B
Vest4		0.023
MutPred		0.14		Gain of sheet (P = 0.039)
MVP		0.19
MPC		0.16
ClinPred		0.025	T
GERP RS		-3.0
Varity_R		0.019
gMVP		0.029
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1275973826; hg19: chr6-151669912; COSMIC: COSV99482791;