17-57105546-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003488.4(AKAP1):c.82C>A(p.Arg28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AKAP1 NM_003488.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

Genes affected

AKAP1 (HGNC:367): (A-kinase anchoring protein 1) 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 binds to type I and type II regulatory subunits of PKA and anchors them to the mitochondrion. This protein is speculated to be involved in the cAMP-dependent signal transduction pathway and in directing RNA to a specific cellular compartment. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41875988).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP1	NM_003488.4	c.82C>A	p.Arg28Ser	missense_variant	2/11	ENST00000337714.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP1	ENST00000337714.8	c.82C>A	p.Arg28Ser	missense_variant	2/11	1	NM_003488.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 77 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2024

The c.82C>A (p.R28S) alteration is located in exon 3 (coding exon 1) of the AKAP1 gene. This alteration results from a C to A substitution at nucleotide position 82, causing the arginine (R) at amino acid position 28 to be replaced by a serine (S). 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	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T;T;T;.;.;.;T;T;.;.;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;.;.;D;D;D;D;.;.;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.90	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.;.;D;D;.;.;.
Vest4		0.93, 0.93, 0.68
MutPred		0.53		Gain of glycosylation at R28 (P = 0.0155);Gain of glycosylation at R28 (P = 0.0155);Gain of glycosylation at R28 (P = 0.0155);Gain of glycosylation at R28 (P = 0.0155);Gain of glycosylation at R28 (P = 0.0155);Gain of glycosylation at R28 (P = 0.0155);Gain of glycosylation at R28 (P = 0.0155);Gain of glycosylation at R28 (P = 0.0155);Gain of glycosylation at R28 (P = 0.0155);Gain of glycosylation at R28 (P = 0.0155);Gain of glycosylation at R28 (P = 0.0155);Gain of glycosylation at R28 (P = 0.0155);
MVP		0.64
MPC		0.92
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.53
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-55182907;