chr14-64468908-C-A

Variant names:

• chr14-64468908-C-A
• NM_004857.3:c.514C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004857.3(AKAP5):​c.514C>A​(p.Gln172Lys) 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 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q172R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AKAP5 NM_004857.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.123

Genes affected

AKAP5 (HGNC:375): (A-kinase anchoring protein 5) 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 the RII-beta regulatory subunit of PKA, and also to protein kinase C and the phosphatase calcineurin. It is predominantly expressed in cerebral cortex and may anchor the PKA protein at postsynaptic densities (PSD) and be involved in the regulation of postsynaptic events. It is also expressed in T lymphocytes and may function to inhibit interleukin-2 transcription by disrupting calcineurin-dependent dephosphorylation of NFAT. [provided by RefSeq, Jul 2008]

ZBTB25 (HGNC:13112): (zinc finger and BTB domain containing 25) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06188312).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP5	NM_004857.3	c.514C>A	p.Gln172Lys	missense_variant	Exon 2 of 2	ENST00000394718.4	NP_004848.3
ZBTB25	NM_001304508.1	c.174-19270G>T		intron_variant	Intron 2 of 2		NP_001291437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP5	ENST00000394718.4	c.514C>A	p.Gln172Lys	missense_variant	Exon 2 of 2	1	NM_004857.3	ENSP00000378207.3
ZBTB25	ENST00000555220.5	c.174-19270G>T		intron_variant	Intron 2 of 2	1		ENSP00000450718.1
AKAP5	ENST00000320636.5	c.514C>A	p.Gln172Lys	missense_variant	Exon 1 of 1	6		ENSP00000315615.5
ZBTB25	ENST00000555424.1	c.256+18206G>T		intron_variant	Intron 2 of 2	5		ENSP00000451046.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727218

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000122 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514C>A (p.Q172K) alteration is located in exon 2 (coding exon 1) of the AKAP5 gene. This alteration results from a C to A substitution at nucleotide position 514, causing the glutamine (Q) at amino acid position 172 to be replaced by a lysine (K). 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	0.071
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.7
DANN	Benign	0.83
DEOGEN2	Benign	0.41	T;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.38	.;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.11
Sift	Benign	0.39	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.0030	B;B
Vest4		0.074
MutPred		0.15		Gain of ubiquitination at Q172 (P = 0.0082);Gain of ubiquitination at Q172 (P = 0.0082);
MVP		0.54
MPC		0.26
ClinPred		0.058	T
GERP RS		0.71
Varity_R		0.13
gMVP		0.14

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: chr14-64935626;