15-85579068-G-A

Variant summary

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

The NM_007200.5(AKAP13):c.1000G>A(p.Glu334Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,142 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (9 hom.)
• Consequence: AKAP13 NM_007200.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038051903).
• BP6: Variant 15-85579068-G-A is Benign according to our data. Variant chr15-85579068-G-A is described in ClinVar as [Benign]. Clinvar id is 770627.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00666 (1014/152252) while in subpopulation AFR AF= 0.0235 (976/41542). AF 95% confidence interval is 0.0223. There are 18 homozygotes in gnomad4. There are 515 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP13	NM_007200.5	c.1000G>A	p.Glu334Lys	missense_variant	7/37	ENST00000394518.7
AKAP13	NM_006738.6	c.1000G>A	p.Glu334Lys	missense_variant	7/37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP13	ENST00000394518.7	c.1000G>A	p.Glu334Lys	missense_variant	7/37	1	NM_007200.5	A2
	ENST00000561409.1	n.931C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1014 AN: 152134 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00146 AC: 366 AN: 251272 Hom.: 3 AF XY: 0.00102 AC XY: 139 AN XY: 135824

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.000636

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: 0.00000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000700 AC: 1024 AN: 1461890 Hom.: 9 Cov.: 30 AF XY: 0.000615 AC XY: 447 AN XY: 727246

Gnomad4 AFR exome AF: 0.0268

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00666 AC: 1014 AN: 152252 Hom.: 18 Cov.: 32 AF XY: 0.00692 AC XY: 515 AN XY: 74446

Gnomad4 AFR AF: 0.0235

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00157 Hom.: 3

Bravo AF: 0.00754

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00183 AC: 222

Asia WGS AF: 0.000866 AC: 4 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

Apr 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.021	T;T;.;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.76	T;T;T;T;T
MetaRNN	Benign	0.0038	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.9	N;N;N;.;.
Sift	Uncertain	0.0070	D;D;D;.;.
Sift4G	Benign	0.14	T;T;T;D;T
Polyphen		0.0010, 0.0020	.;B;B;.;.
Vest4		0.042, 0.035
MVP		0.37
MPC		0.12
ClinPred		0.021	T
GERP RS		0.35
Varity_R		0.061
gMVP		0.17

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: rs73452430; hg19: chr15-86122299;