12-4627140-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001278309.2(AKAP3):ā€‹c.1762A>Gā€‹(p.Lys588Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

AKAP3
NM_001278309.2 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.30
Variant links:
Genes affected
AKAP3 (HGNC:373): (A-kinase anchoring protein 3) This gene encodes a member of A-kinase anchoring proteins (AKAPs), a family of functionally related proteins that target protein kinase A to discrete locations within the cell. The encoded protein is reported to participate in protein-protein interactions with the R-subunit of the protein kinase A as well as sperm-associated proteins. This protein is expressed in spermatozoa and localized to the acrosomal region of the sperm head as well as the length of the principal piece. It may function as a regulator of motility, capacitation, and the acrosome reaction. [provided by RefSeq, May 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AKAP3NM_001278309.2 linkc.1762A>G p.Lys588Glu missense_variant 5/6 ENST00000228850.6 NP_001265238.2 O75969V9HWD4
AKAP3NM_006422.4 linkc.1762A>G p.Lys588Glu missense_variant 5/6 NP_006413.4 O75969V9HWD4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AKAP3ENST00000228850.6 linkc.1762A>G p.Lys588Glu missense_variant 5/65 NM_001278309.2 ENSP00000228850.1 O75969
ENSG00000272921ENST00000536588.1 linkn.142-4182T>C intron_variant 3 ENSP00000445121.1 H0YGX0
AKAP3ENST00000545990.6 linkc.1762A>G p.Lys588Glu missense_variant 5/62 ENSP00000440994.1 O75969

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251152
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135772
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
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:
6.84e-7
AC:
1
AN:
1461880
Hom.:
0
Cov.:
75
AF XY:
0.00000138
AC XY:
1
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

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 submitterclinical testingAmbry GeneticsMar 15, 2024The c.1762A>G (p.K588E) alteration is located in exon 4 (coding exon 2) of the AKAP3 gene. This alteration results from a A to G substitution at nucleotide position 1762, causing the lysine (K) at amino acid position 588 to be replaced by a glutamic acid (E). 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
0.17
BayesDel_addAF
Benign
-0.095
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0082
T;T
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.76
.;T
M_CAP
Benign
0.0053
T
MetaRNN
Uncertain
0.45
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.7
M;M
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.17
Sift
Benign
0.24
T;T
Sift4G
Benign
0.39
T;T
Polyphen
0.99
D;D
Vest4
0.42
MutPred
0.53
Loss of ubiquitination at K588 (P = 0.0098);Loss of ubiquitination at K588 (P = 0.0098);
MVP
0.51
MPC
0.67
ClinPred
0.86
D
GERP RS
4.8
Varity_R
0.15
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

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

Other links and lift over

dbSNP: rs768885148; hg19: chr12-4736306; API