6-151349203-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005100.4(AKAP12):c.812A>G(p.Glu271Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00296 in 1,613,924 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0031 (54 hom.)
• Consequence: AKAP12 NM_005100.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.28

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=0.00404191).
• BP6: Variant 6-151349203-A-G is Benign according to our data. Variant chr6-151349203-A-G is described in ClinVar as [Benign]. Clinvar id is 721150.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00187 (285/152312) while in subpopulation SAS AF= 0.0214 (103/4820). AF 95% confidence interval is 0.018. There are 6 homozygotes in gnomad4. There are 158 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP12	NM_005100.4	c.812A>G	p.Glu271Gly	missense_variant	4/5	ENST00000402676.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP12	ENST00000402676.7	c.812A>G	p.Glu271Gly	missense_variant	4/5	5	NM_005100.4	A2

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152194 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00432 AC: 1078 AN: 249718 Hom.: 20 AF XY: 0.00536 AC XY: 726 AN XY: 135402

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.000501

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0242

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00280

GnomAD4 exome AF: 0.00307 AC: 4485 AN: 1461612 Hom.: 54 Cov.: 74 AF XY: 0.00382 AC XY: 2779 AN XY: 727092

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00187 AC: 285 AN: 152312 Hom.: 6 Cov.: 31 AF XY: 0.00212 AC XY: 158 AN XY: 74488

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0214

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00207 Hom.: 2

Bravo AF: 0.00176

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00461 AC: 560

Asia WGS AF: 0.00751 AC: 27 AN: 3478

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

May 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.80	T;.;T;T
MetaRNN	Benign	0.0040	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.4	L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Benign	0.014
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.055	B;B;B;B
Vest4		0.16
MVP		0.19
MPC		0.23
ClinPred		0.021	T
GERP RS		1.2
Varity_R		0.13
gMVP		0.043

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: rs61757550; hg19: chr6-151670338;