Genetic Variant AKAP8:p.Ala615Ala (chr19-15355149-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005858.4(AKAP8):c.1845C>T(p.Ala615Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,050 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 16 hom. )

Consequence

AKAP8
NM_005858.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.121

Publications

1 publications found

Variant links:

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]

AKAP8 links:

LOC124904643 (HGNC:):

LOC124904643 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 19-15355149-G-A is Benign according to our data. Variant chr19-15355149-G-A is described in ClinVar as [Benign]. Clinvar id is 718804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.121 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00175 (267/152240) while in subpopulation EAS AF = 0.0271 (140/5172). AF 95% confidence interval is 0.0234. There are 5 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP8	NM_005858.4 link	c.1845C>T	p.Ala615Ala	synonymous_variant	Exon 14 of 14	ENST00000269701.7	NP_005849.1	O43823
LOC124904643	XR_007067146.1 link	n.286-6902G>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP8	ENST00000269701.7 link	c.1845C>T	p.Ala615Ala	synonymous_variant	Exon 14 of 14	1	NM_005858.4	ENSP00000269701.1		O43823

Frequencies

GnomAD3 genomes

AF:

0.00174

AC:

264

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0268

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00502

AC:

1257

AN:

250404

AF XY:

0.00399

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0196

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0297

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00115

AC:

1682

AN:

1460810

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

744

AN XY:

726758

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.0184

AC:

823

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0178

AC:

706

AN:

39700

South Asian (SAS)

AF:

0.000591

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1112008

Other (OTH)

AF:

0.00106

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

128

255

383

510

638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00175

AC:

267

AN:

152240

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

171

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41542

American (AMR)

AF:

0.00726

AC:

111

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0271

AC:

140

AN:

5172

South Asian (SAS)

AF:

0.00166

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000663

Hom.:

Bravo

AF:

0.00310

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.1

(source)

DANN

Benign

0.50

PhyloP100

0.12

Mutation Taster

=100/0

polymorphism

(source)

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

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chr19-15355149-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over