15-85655615-A-G

Position:

• chr15-85655615-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007200.5(AKAP13):​c.4573A>G​(p.Ser1525Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,614,194 control chromosomes in the GnomAD database, including 143 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (82 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (61 hom.)
• Consequence: AKAP13 NM_007200.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.05

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]

AKAP13-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017677248).
• BP6: Variant 15-85655615-A-G is Benign according to our data. Variant chr15-85655615-A-G is described in ClinVar as [Benign]. Clinvar id is 710072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP13	NM_007200.5	c.4573A>G	p.Ser1525Gly	missense_variant	11/37	ENST00000394518.7	NP_009131.2
AKAP13	NM_006738.6	c.4573A>G	p.Ser1525Gly	missense_variant	11/37		NP_006729.4
AKAP13	NM_001270546.1	c.493A>G	p.Ser165Gly	missense_variant	4/29		NP_001257475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP13	ENST00000394518.7	c.4573A>G	p.Ser1525Gly	missense_variant	11/37	1	NM_007200.5	ENSP00000378026.3

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2728 AN: 152186 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.0620

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00466 AC: 1172 AN: 251470 Hom.: 36 AF XY: 0.00335 AC XY: 455 AN XY: 135912

Gnomad AFR exome AF: 0.0637

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00191 AC: 2789 AN: 1461890 Hom.: 61 Cov.: 31 AF XY: 0.00161 AC XY: 1174 AN XY: 727246

Gnomad4 AFR exome AF: 0.0623

Gnomad4 AMR exome AF: 0.00371

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000264

Gnomad4 OTH exome AF: 0.00371

GnomAD4 genome AF: 0.0179 AC: 2729 AN: 152304 Hom.: 82 Cov.: 32 AF XY: 0.0170 AC XY: 1267 AN XY: 74482

Gnomad4 AFR AF: 0.0619

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00339 Hom.: 25

Bravo AF: 0.0209

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0658 AC: 290

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00563 AC: 684

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0079	T;T;.;.;T;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.75	T;T;T;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L;L;.;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;N;N;.;D;.;N
REVEL	Benign	0.10
Sift	Benign	0.16	T;T;T;.;T;.;T
Sift4G	Benign	0.32	T;T;T;T;T;T;T
Polyphen		0.012, 0.021	.;B;B;.;.;.;.
Vest4		0.18, 0.15, 0.12, 0.25
MVP		0.49
MPC		0.036
ClinPred		0.0022	T
GERP RS		3.7
Varity_R		0.051
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs35079107; hg19: chr15-86198846;