rs745191

chr15-85579939-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007200.5(AKAP13):c.1871G>T(p.Gly624Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,613,956 control chromosomes in the GnomAD database, including 55,321 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (4148 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51173 hom.)
• Consequence: AKAP13 NM_007200.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.250

Genes affected

AKAP13 (HGNC:371): (A-kinase anchoring protein 13) 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. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms containing c-terminal dbl oncogene homology (DH) and pleckstrin homology (PH) domains. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. Therefore, these isoforms function as scaffolding proteins to coordinate a Rho signaling pathway, function as protein kinase A-anchoring proteins and, in addition, enhance ligand-dependent activity of estrogen receptors alpha and beta. [provided by RefSeq, Jul 2012]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003947228).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP13	NM_007200.5	c.1871G>T	p.Gly624Val	missense_variant	7/37	ENST00000394518.7
AKAP13	NM_006738.6	c.1871G>T	p.Gly624Val	missense_variant	7/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP13	ENST00000394518.7	c.1871G>T	p.Gly624Val	missense_variant	7/37	1	NM_007200.5	A2
AKAP13	ENST00000361243.6	c.1871G>T	p.Gly624Val	missense_variant	7/37	1		A2
	ENST00000561409.1	n.159+81C>A		intron_variant, non_coding_transcript_variant		3
AKAP13	ENST00000559362.5	c.1871G>T	p.Gly624Val	missense_variant	7/15	2

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30878 AN: 152004 Hom.: 4152 Cov.: 32

Gnomad AFR AF: 0.0479

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.286

Gnomad OTH AF: 0.250

GnomAD3 exomes AF: 0.228 AC: 57291 AN: 250856 Hom.: 7851 AF XY: 0.237 AC XY: 32111 AN XY: 135604

Gnomad AFR exome AF: 0.0419

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.0269

Gnomad SAS exome AF: 0.197

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.256 AC: 373697 AN: 1461834 Hom.: 51173 Cov.: 81 AF XY: 0.256 AC XY: 186140 AN XY: 727216

Gnomad4 AFR exome AF: 0.0434

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.398

Gnomad4 EAS exome AF: 0.0208

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.275

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.203 AC: 30875 AN: 152122 Hom.: 4148 Cov.: 32 AF XY: 0.200 AC XY: 14875 AN XY: 74342

Gnomad4 AFR AF: 0.0478

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.0235

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.286

Gnomad4 OTH AF: 0.247

Alfa AF: 0.279 Hom.: 14584

Bravo AF: 0.195

TwinsUK AF: 0.259 AC: 962

ALSPAC AF: 0.270 AC: 1040

ESP6500AA AF: 0.0481 AC: 212

ESP6500EA AF: 0.284 AC: 2442

ExAC AF: 0.228 AC: 27629

Asia WGS AF: 0.102 AC: 354 AN: 3478

EpiCase AF: 0.307

EpiControl AF: 0.311

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	6.9
Dann	Benign	0.94
DEOGEN2	Benign	0.026	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.61	T;T;T
MetaRNN	Benign	0.0039	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.8	D;D;D
Sift	Uncertain	0.014	D;D;D
Sift4G	Benign	0.15	T;D;D
Polyphen		0.0010	.;B;B
Vest4		0.12, 0.083
MPC		0.19
ClinPred		0.023	T
GERP RS		0.36
Varity_R		0.17
gMVP		0.24

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: rs745191; hg19: chr15-86123170; COSMIC: COSV63448180; COSMIC: COSV63448180;