chr19-15355229-C-T

Variant names:

• chr19-15355229-C-T
• rs150076099
• NM_005858.4:c.1765G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005858.4(AKAP8):​c.1765G>A​(p.Val589Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,611,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: AKAP8 NM_005858.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94
• Publications: 1 publications found

Genes affected

AKAP8 (HGNC:378): (A-kinase anchoring protein 8) This gene encodes a member of the A-kinase anchor protein family. A-kinase anchor proteins are scaffold proteins that contain a binding domain for the RI/RII subunit of protein kinase A (PKA) and recruit PKA and other signaling molecules to specific subcellular locations. This gene encodes a nuclear A-kinase anchor protein that binds to the RII alpha subunit of PKA and may play a role in chromosome condensation during mitosis by targeting PKA and the condensin complex to chromatin. A pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, May 2011]

LOC124904643 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12955734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP8	NM_005858.4	c.1765G>A	p.Val589Ile	missense_variant	Exon 14 of 14	ENST00000269701.7	NP_005849.1
LOC124904643	XR_007067146.1	n.286-6822C>T		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP8	ENST00000269701.7	c.1765G>A	p.Val589Ile	missense_variant	Exon 14 of 14	1	NM_005858.4	ENSP00000269701.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000401 AC: 10 AN: 249276 AF XY: 0.0000222

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1459148 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 726072

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000394 AC: 2 AN: 50704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74374

African (AFR) AF: 0.000241 AC: 10 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000272 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1765G>A (p.V589I) alteration is located in exon 14 (coding exon 14) of the AKAP8 gene. This alteration results from a G to A substitution at nucleotide position 1765, causing the valine (V) at amino acid position 589 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	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.0041
Eigen_PC	Benign	-0.046
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		2.9
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.089
Sift	Uncertain	0.010	D
Sift4G	Benign	0.15	T
Polyphen		0.95	P
Vest4		0.24
MVP		0.38
MPC		0.44
ClinPred		0.52	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.090
gMVP		0.14
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs150076099; hg19: chr19-15466040;