rs2061821

Variant names:

• chr15-85579423-T-C
• rs2061821
• NM_007200.5:c.1355T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007200.5(AKAP13):​c.1355T>C​(p.Met452Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 1,613,822 control chromosomes in the GnomAD database, including 322,938 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M452V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.62 (28930 hom., cov: 32)
  • Exomes 𝑓: 0.63 (294008 hom.)
• Consequence: AKAP13 NM_007200.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 46 publications found

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]

ENSG00000259375 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.007797E-6).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP13	NM_007200.5	c.1355T>C	p.Met452Thr	missense_variant	Exon 7 of 37	ENST00000394518.7	NP_009131.2
AKAP13	NM_006738.6	c.1355T>C	p.Met452Thr	missense_variant	Exon 7 of 37		NP_006729.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP13	ENST00000394518.7	c.1355T>C	p.Met452Thr	missense_variant	Exon 7 of 37	1	NM_007200.5	ENSP00000378026.3

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93428 AN: 151862 Hom.: 28912 Cov.: 32

Gnomad AFR AF: 0.591

Gnomad AMI AF: 0.661

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.723

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.639

GnomAD2 exomes AF: 0.607 AC: 152552 AN: 251302 AF XY: 0.610

Gnomad AFR exome AF: 0.583

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.709

Gnomad EAS exome AF: 0.581

Gnomad FIN exome AF: 0.511

Gnomad NFE exome AF: 0.649

Gnomad OTH exome AF: 0.631

GnomAD4 exome AF: 0.633 AC: 924991 AN: 1461842 Hom.: 294008 Cov.: 82 AF XY: 0.632 AC XY: 459476 AN XY: 727224

African (AFR) AF: 0.594 AC: 19902 AN: 33480

American (AMR) AF: 0.565 AC: 25250 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 18594 AN: 26136

East Asian (EAS) AF: 0.608 AC: 24119 AN: 39700

South Asian (SAS) AF: 0.568 AC: 49019 AN: 86258

European-Finnish (FIN) AF: 0.516 AC: 27538 AN: 53418

Middle Eastern (MID) AF: 0.689 AC: 3971 AN: 5766

European-Non Finnish (NFE) AF: 0.646 AC: 718635 AN: 1111970

Other (OTH) AF: 0.629 AC: 37963 AN: 60394

GnomAD4 genome AF: 0.615 AC: 93492 AN: 151980 Hom.: 28930 Cov.: 32 AF XY: 0.608 AC XY: 45131 AN XY: 74276

African (AFR) AF: 0.591 AC: 24488 AN: 41416

American (AMR) AF: 0.610 AC: 9309 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.723 AC: 2506 AN: 3468

East Asian (EAS) AF: 0.595 AC: 3070 AN: 5158

South Asian (SAS) AF: 0.556 AC: 2682 AN: 4820

European-Finnish (FIN) AF: 0.508 AC: 5359 AN: 10558

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.646 AC: 43922 AN: 67976

Other (OTH) AF: 0.636 AC: 1341 AN: 2110

Alfa AF: 0.643 Hom.: 105074

Bravo AF: 0.620

TwinsUK AF: 0.649 AC: 2406

ALSPAC AF: 0.630 AC: 2428

ESP6500AA AF: 0.594 AC: 2614

ESP6500EA AF: 0.644 AC: 5540

ExAC AF: 0.610 AC: 74115

Asia WGS AF: 0.562 AC: 1955 AN: 3478

EpiCase AF: 0.659

EpiControl AF: 0.660

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.5
DANN	Benign	0.75
DEOGEN2	Benign	0.012	T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.47	T;T;T
MetaRNN	Benign	0.0000050	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	.;L;L
PhyloP100		-1.1
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.76	N;N;N
REVEL	Benign	0.078
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0020, 0.0030	.;B;B
Vest4		0.024, 0.0090
MPC		0.041
ClinPred		0.0091	T
GERP RS		-8.7
Varity_R		0.033
gMVP		0.14
Mutation Taster		=96/4	polymorphism (auto)

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: rs2061821; hg19: chr15-86122654; COSMIC: COSV63448142; COSMIC: COSV63448142;