NM_007202.4:c.746G>A

Variant names:

• chr17-19958145-C-T
• rs2108978
• NM_007202.4:c.746G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• 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
• Publications: 53 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
AKAP10	NM_007202.4	c.746G>A	p.Arg249His	missense_variant	Exon 4 of 15	ENST00000225737.11	NP_009133.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP10	ENST00000225737.11	c.746G>A	p.Arg249His	missense_variant	Exon 4 of 15	1	NM_007202.4	ENSP00000225737.6
AKAP10	ENST00000395536.7	c.746G>A	p.Arg249His	missense_variant	Exon 4 of 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

GnomAD2 exomes AF: 0.370 AC: 93125 AN: 251468 AF XY: 0.363

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 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

African (AFR) AF: 0.577 AC: 19334 AN: 33480

American (AMR) AF: 0.419 AC: 18719 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 9469 AN: 26134

East Asian (EAS) AF: 0.202 AC: 8032 AN: 39698

South Asian (SAS) AF: 0.303 AC: 26114 AN: 86254

European-Finnish (FIN) AF: 0.346 AC: 18478 AN: 53418

Middle Eastern (MID) AF: 0.403 AC: 2327 AN: 5768

European-Non Finnish (NFE) AF: 0.393 AC: 436602 AN: 1111982

Other (OTH) AF: 0.387 AC: 23371 AN: 60396

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

African (AFR) AF: 0.569 AC: 23542 AN: 41410

American (AMR) AF: 0.429 AC: 6548 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1263 AN: 3470

East Asian (EAS) AF: 0.190 AC: 980 AN: 5166

South Asian (SAS) AF: 0.286 AC: 1378 AN: 4814

European-Finnish (FIN) AF: 0.350 AC: 3688 AN: 10546

Middle Eastern (MID) AF: 0.414 AC: 120 AN: 290

European-Non Finnish (NFE) AF: 0.376 AC: 25567 AN: 67942

Other (OTH) AF: 0.411 AC: 866 AN: 2108

Alfa AF: 0.398 Hom.: 39899

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

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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;.
PhyloP100		0.20
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
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: rs2108978; hg19: chr17-19861458; COSMIC: COSV56731351; COSMIC: COSV56731351;