14-64468422-G-A

Position:

• chr14-64468422-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004857.3(AKAP5):​c.28G>A​(p.Val10Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000758 in 1,451,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: AKAP5 NM_004857.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07105067).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKAP5	NM_004857.3	c.28G>A	p.Val10Ile	missense_variant	2/2	ENST00000394718.4	NP_004848.3
ZBTB25	NM_001304508.1	c.174-18784C>T		intron_variant			NP_001291437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKAP5	ENST00000394718.4	c.28G>A	p.Val10Ile	missense_variant	2/2	1	NM_004857.3	ENSP00000378207.3
ZBTB25	ENST00000555220.5	c.174-18784C>T		intron_variant		1		ENSP00000450718.1
AKAP5	ENST00000320636.5	c.28G>A	p.Val10Ile	missense_variant	1/1	6		ENSP00000315615.5
ZBTB25	ENST00000555424.1	c.256+18692C>T		intron_variant		5		ENSP00000451046.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000758 AC: 11 AN: 1451762 Hom.: 0 Cov.: 29 AF XY: 0.00000970 AC XY: 7 AN XY: 722012

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: 0.00000631

Gnomad4 OTH exome AF: 0.0000668

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

Mar 29, 2022

The c.28G>A (p.V10I) alteration is located in exon 2 (coding exon 1) of the AKAP5 gene. This alteration results from a G to A substitution at nucleotide position 28, causing the valine (V) at amino acid position 10 to be replaced by an isoleucine (I). 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	0.091
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.52	.;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.071	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.54	N;N
REVEL	Benign	0.013
Sift	Benign	0.28	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.087	B;B
Vest4		0.11
MutPred		0.22		Gain of catalytic residue at I5 (P = 0.0021);Gain of catalytic residue at I5 (P = 0.0021);
MVP		0.53
MPC		0.20
ClinPred		0.17	T
GERP RS		2.7
Varity_R		0.040
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: chr14-64935140;