17-19909228-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_007202.4(AKAP10):c.1936A>G(p.Ile646Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 1,612,096 control chromosomes in the GnomAD database, including 125,833 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (14762 hom., cov: 33)
  • Exomes 𝑓: 0.39 (111071 hom.)
• Consequence: AKAP10 NM_007202.4 missense
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 3.39

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.4074975E-5).
• BP6: Variant 17-19909228-T-C is Benign according to our data. Variant chr17-19909228-T-C is described in ClinVar as [Benign]. Clinvar id is 5404.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP10	NM_007202.4	c.1936A>G	p.Ile646Val	missense_variant	14/15	ENST00000225737.11
AKAP10	NM_001330152.2	c.1762A>G	p.Ile588Val	missense_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP10	ENST00000225737.11	c.1936A>G	p.Ile646Val	missense_variant	14/15	1	NM_007202.4	P1
AKAP10	ENST00000395536.7	c.1762A>G	p.Ile588Val	missense_variant	13/14	5
AKAP10	ENST00000578898.1	c.*269A>G		3_prime_UTR_variant, NMD_transcript_variant	5/6	3
AKAP10	ENST00000583951.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64970 AN: 151984 Hom.: 14728 Cov.: 33

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.416

GnomAD3 exomes AF: 0.371 AC: 93016 AN: 250460 Hom.: 18352 AF XY: 0.364 AC XY: 49250 AN XY: 135416

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.417

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.182

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: 562722 AN: 1459994 Hom.: 111071 Cov.: 37 AF XY: 0.382 AC XY: 277236 AN XY: 726326

Gnomad4 AFR exome AF: 0.595

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.368

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: 0.389

GnomAD4 genome AF: 0.428 AC: 65059 AN: 152102 Hom.: 14762 Cov.: 33 AF XY: 0.424 AC XY: 31542 AN XY: 74368

Gnomad4 AFR AF: 0.584

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.370

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.287

Gnomad4 FIN AF: 0.348

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.415

Alfa AF: 0.385 Hom.: 30014

Bravo AF: 0.444

TwinsUK AF: 0.402 AC: 1490

ALSPAC AF: 0.406 AC: 1564

ESP6500AA AF: 0.581 AC: 2560

ESP6500EA AF: 0.383 AC: 3298

ExAC AF: 0.373 AC: 45349

Asia WGS AF: 0.242 AC: 847 AN: 3478

EpiCase AF: 0.386

EpiControl AF: 0.374

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiac conduction defect, susceptibility to Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

May 15, 2007

- -

AKAP10-related disorder Benign:1

Benign, criteria provided, single submitter

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	0.048
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	16
Dann	Benign	0.49
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.000054	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.0	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.31	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.12
MPC		0.18
ClinPred		0.0060	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.19

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: rs203462; hg19: chr17-19812541; COSMIC: COSV56731343; COSMIC: COSV56731343;