17-57105823-G-A

Variant names:

• chr17-57105823-G-A
• rs373591740
• NM_003488.4:c.359G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003488.4(AKAP1):​c.359G>A​(p.Arg120Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: AKAP1 NM_003488.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.296

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021211833).
• BP6: Variant 17-57105823-G-A is Benign according to our data. Variant chr17-57105823-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3104454.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP1	NM_003488.4	c.359G>A	p.Arg120Gln	missense_variant	Exon 2 of 11	ENST00000337714.8	NP_003479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP1	ENST00000337714.8	c.359G>A	p.Arg120Gln	missense_variant	Exon 2 of 11	1	NM_003488.4	ENSP00000337736.3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251406 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135894

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461884 Hom.: 0 Cov.: 77 AF XY: 0.0000316 AC XY: 23 AN XY: 727242

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74352

Gnomad4 AFR AF: 0.000435

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 02, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	2.2
DANN	Benign	0.94
DEOGEN2	Benign	0.063	T;T;T;T;.;T;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.73	T;.;.;T;T;.;.;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.021	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.66	.;N;N;N;.;N;N;N;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.47	.;N;.;.;.;.;N;N;.
REVEL	Benign	0.016
Sift	Benign	1.0	.;T;.;.;.;.;T;T;.
Sift4G	Benign	0.60	T;T;T;T;T;T;T;T;T
Polyphen		0.11	.;B;B;B;.;B;B;.;.
Vest4		0.054, 0.052, 0.051, 0.050, 0.032
MVP		0.34
MPC		0.27
ClinPred		0.0087	T
GERP RS		-2.1
Varity_R		0.015
gMVP		0.066

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

LitVar

Other links and lift over

dbSNP: rs373591740; hg19: chr17-55183184; COSMIC: COSV100028223; COSMIC: COSV100028223;