17-19958145-C-T

Position:

• chr17-19958145-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_007202.4(AKAP10):​c.746G>A​(p.Arg249His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 1,613,756 control chromosomes in the GnomAD database, including 124,899 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.42 (14347 hom., cov: 31)
  • Exomes 𝑓: 0.38 (110552 hom.)
• Consequence: AKAP10 NM_007202.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.200

Genes affected

AKAP10 (HGNC:368): (A-kinase anchoring protein 10) This gene encodes a member of the A-kinase anchor protein family. A-kinase anchor proteins bind to the regulatory subunits of protein kinase A (PKA) and confine the holoenzyme to discrete locations within the cell. The encoded protein is localized to mitochondria and interacts with both the type I and type II regulatory subunits of PKA. Polymorphisms in this gene may be associated with increased risk of arrhythmias and sudden cardiac death. [provided by RefSeq, May 2012]

AKAP10 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.11504865E-4).
• BP6: Variant 17-19958145-C-T is Benign according to our data. Variant chr17-19958145-C-T is described in ClinVar as [Benign]. Clinvar id is 3059344.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP10	NM_007202.4	c.746G>A	p.Arg249His	missense_variant	4/15	ENST00000225737.11	NP_009133.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP10	ENST00000225737.11	c.746G>A	p.Arg249His	missense_variant	4/15	1	NM_007202.4	ENSP00000225737.6
AKAP10	ENST00000395536.7	c.746G>A	p.Arg249His	missense_variant	4/14	5		ENSP00000378907.3

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64205 AN: 151784 Hom.: 14324 Cov.: 31

Gnomad AFR AF: 0.568

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.412

GnomAD3 exomes AF: 0.370 AC: 93125 AN: 251468 Hom.: 18237 AF XY: 0.363 AC XY: 49309 AN XY: 135902

Gnomad AFR exome AF: 0.574

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.297

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.385 AC: 562446 AN: 1461854 Hom.: 110552 Cov.: 60 AF XY: 0.381 AC XY: 277054 AN XY: 727226

Gnomad4 AFR exome AF: 0.577

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.362

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.303

Gnomad4 FIN exome AF: 0.346

Gnomad4 NFE exome AF: 0.393

Gnomad4 OTH exome AF: 0.387

GnomAD4 genome AF: 0.423 AC: 64281 AN: 151902 Hom.: 14347 Cov.: 31 AF XY: 0.420 AC XY: 31179 AN XY: 74228

Gnomad4 AFR AF: 0.569

Gnomad4 AMR AF: 0.429

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.350

Gnomad4 NFE AF: 0.376

Gnomad4 OTH AF: 0.411

Alfa AF: 0.386 Hom.: 25368

Bravo AF: 0.439

TwinsUK AF: 0.402 AC: 1491

ALSPAC AF: 0.406 AC: 1565

ESP6500AA AF: 0.565 AC: 2491

ESP6500EA AF: 0.383 AC: 3296

ExAC AF: 0.372 AC: 45130

Asia WGS AF: 0.238 AC: 831 AN: 3478

EpiCase AF: 0.386

EpiControl AF: 0.373

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

AKAP10-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.53
DEOGEN2	Benign	0.046	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.00011	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.2	N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.0	N;N
REVEL	Benign	0.030
Sift	Benign	1.0	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0	B;B
Vest4		0.020
MPC		0.27
ClinPred		0.00088	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.014
gMVP		0.20

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: rs2108978; hg19: chr17-19861458; COSMIC: COSV56731351; COSMIC: COSV56731351;