Variant 14-32545713-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004274.5(AKAP6):c.1060C>G(p.His354Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

AKAP6
NM_004274.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.779

Variant links:

Genes affected

AKAP6 (HGNC:376): (A-kinase anchoring protein 6) 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. The encoded protein is highly expressed in various brain regions and cardiac and skeletal muscle. It is specifically localized to the sarcoplasmic reticulum and nuclear membrane, and is involved in anchoring PKA to the nuclear membrane or sarcoplasmic reticulum. [provided by RefSeq, Jul 2008]

AKAP6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04181686).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP6	NM_004274.5 linkuse as main transcript	c.1060C>G	p.His354Asp	missense_variant	4/14	ENST00000280979.9	NP_004265.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP6	ENST00000280979.9 linkuse as main transcript	c.1060C>G	p.His354Asp	missense_variant	4/14	1	NM_004274.5	ENSP00000280979	P1	Q13023-1
AKAP6	ENST00000557354.5 linkuse as main transcript	c.1060C>G	p.His354Asp	missense_variant	4/10	1		ENSP00000450531		Q13023-2
AKAP6	ENST00000557272.1 linkuse as main transcript	c.1060C>G	p.His354Asp	missense_variant	4/13	5		ENSP00000451247
AKAP6	ENST00000553547.5 linkuse as main transcript	c.334C>G	p.His112Asp	missense_variant	3/3	2		ENSP00000451239

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250600

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135556

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.1060C>G (p.H354D) alteration is located in exon 4 (coding exon 3) of the AKAP6 gene. This alteration results from a C to G substitution at nucleotide position 1060, causing the histidine (H) at amino acid position 354 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.0

DANN

Benign

0.82

DEOGEN2

Benign

0.026

T;.;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.39

T;T;T;T

M_CAP

Benign

0.0018

MetaRNN

Benign

0.042

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

1.1

N;N;N;N

REVEL

Benign

0.071

Sift

Benign

0.81

T;T;T;T

Sift4G

Benign

0.76

T;T;T;T

Polyphen

0.029

B;.;.;.

Vest4

0.14

MutPred

0.11

Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;

MVP

0.24

MPC

0.084

ClinPred

0.024

GERP RS

4.3

Varity_R

0.050

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over