Variant X-50192872-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000358526.7(AKAP4):c.1841A>G(p.Lys614Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,210,398 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.000030 ( 0 hom. 13 hem. )

Consequence

AKAP4
ENST00000358526.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.56

Variant links:

Genes affected

AKAP4 (HGNC:374): (A-kinase anchoring protein 4) 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 localized to the sperm flagellum and may be involved in the regulation of sperm motility. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

AKAP4 links:

AKAP4 (HGNC:):

AKAP4 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=0.048437804).

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP4	NM_003886.3 linkuse as main transcript	c.1841A>G	p.Lys614Arg	missense_variant	5/6	ENST00000358526.7	NP_003877.2	Q5JQC9-1A0A384MQY7
AKAP4	NM_139289.2 linkuse as main transcript	c.1814A>G	p.Lys605Arg	missense_variant	5/6		NP_647450.1	Q5JQC9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AKAP4	ENST00000358526.7 linkuse as main transcript	c.1841A>G	p.Lys614Arg	missense_variant	5/6	1	NM_003886.3	ENSP00000351327.2	Q5JQC9-1
AKAP4	ENST00000376064.7 linkuse as main transcript	c.1814A>G	p.Lys605Arg	missense_variant	5/6	1		ENSP00000365232.3	Q5JQC9-2
AKAP4	ENST00000481402.5 linkuse as main transcript	n.1953A>G		non_coding_transcript_exon_variant	5/6	1

Frequencies

GnomAD3 genomes

AF:

0.000214

AC:

AN:

112218

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34362

show subpopulations

Gnomad AFR

AF:

0.000680

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000873

AC:

AN:

183284

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

67750

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1098128

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

363488

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.000214

AC:

AN:

112270

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

34424

show subpopulations

Gnomad4 AFR

AF:

0.000679

Gnomad4 AMR

AF:

0.000188

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000272

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

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

Jan 17, 2024

The c.1841A>G (p.K614R) alteration is located in exon 5 (coding exon 5) of the AKAP4 gene. This alteration results from a A to G substitution at nucleotide position 1841, causing the lysine (K) at amino acid position 614 to be replaced by an arginine (R). 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

0.089

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

T;.

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.048

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.25

N;N

REVEL

Benign

0.092

Sift

Benign

0.086

T;T

Sift4G

Benign

0.25

T;T

Polyphen

1.0

D;.

Vest4

0.23

MVP

0.59

MPC

0.35

ClinPred

0.11

GERP RS

5.1

Varity_R

0.10

gMVP

0.065

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