Variant X-50192844-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003886.3(AKAP4):c.1869A>T(p.Lys623Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,194 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

AKAP4
NM_003886.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.432

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20784557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP4	NM_003886.3 link	c.1869A>T	p.Lys623Asn	missense_variant	5/6	ENST00000358526.7	NP_003877.2	Q5JQC9-1A0A384MQY7
AKAP4	NM_139289.2 link	c.1842A>T	p.Lys614Asn	missense_variant	5/6		NP_647450.1	Q5JQC9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AKAP4	ENST00000358526.7 link	c.1869A>T	p.Lys623Asn	missense_variant	5/6	1	NM_003886.3	ENSP00000351327.2	Q5JQC9-1
AKAP4	ENST00000376064.7 link	c.1842A>T	p.Lys614Asn	missense_variant	5/6	1		ENSP00000365232.3	Q5JQC9-2
AKAP4	ENST00000481402.5 link	n.1981A>T		non_coding_transcript_exon_variant	5/6	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363554

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

Cov.:

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

May 13, 2024

The c.1869A>T (p.K623N) alteration is located in exon 5 (coding exon 5) of the AKAP4 gene. This alteration results from a A to T substitution at nucleotide position 1869, causing the lysine (K) at amino acid position 623 to be replaced by an asparagine (N). 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

Uncertain

0.42

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.5

DANN

Benign

0.90

DEOGEN2

Benign

0.17

T;.

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.64

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.92

N;N

REVEL

Benign

0.11

Sift

Benign

0.035

D;D

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.77

P;.

Vest4

0.075

MutPred

0.74

Loss of ubiquitination at K623 (P = 0.0041);.;

MVP

0.40

MPC

0.18

ClinPred

0.65

GERP RS

-2.6

Varity_R

0.15

gMVP

0.38

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