17-57106452-A-C

Variant names:

• chr17-57106452-A-C
• rs34535433
• NM_003488.4:c.988A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003488.4(AKAP1):​c.988A>C​(p.Ser330Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000693 in 1,442,164 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S330G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000028 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: AKAP1 NM_003488.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.98
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03124103).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003488.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP1	NM_003488.4	MANE Select	c.988A>C	p.Ser330Arg	missense	Exon 2 of 11	NP_003479.1	A0A140VK05
	AKAP1	NM_001242902.2		c.988A>C	p.Ser330Arg	missense	Exon 3 of 12	NP_001229831.1	Q92667-1
	AKAP1	NM_001242903.2		c.988A>C	p.Ser330Arg	missense	Exon 3 of 12	NP_001229832.1	Q92667-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP1	ENST00000337714.8	TSL:1 MANE Select	c.988A>C	p.Ser330Arg	missense	Exon 2 of 11	ENSP00000337736.3	Q92667-1
	AKAP1	ENST00000314126.4	TSL:1	c.988A>C	p.Ser330Arg	missense	Exon 2 of 7	ENSP00000314075.3	Q92667-2
	AKAP1	ENST00000964437.1		c.988A>C	p.Ser330Arg	missense	Exon 2 of 12	ENSP00000634496.1

Frequencies

GnomAD3 genomes AF: 0.0000276 AC: 4 AN: 144770 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000783

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000260 AC: 6 AN: 230600 AF XY: 0.0000242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000462 AC: 6 AN: 1297394 Hom.: 0 Cov.: 34 AF XY: 0.00000771 AC XY: 5 AN XY: 648196

African (AFR) AF: 0.00 AC: 0 AN: 30614

American (AMR) AF: 0.00 AC: 0 AN: 42730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24834

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39566

South Asian (SAS) AF: 0.00 AC: 0 AN: 81320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5462

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 966482

Other (OTH) AF: 0.0000182 AC: 1 AN: 55056

GnomAD4 genome AF: 0.0000276 AC: 4 AN: 144770 Hom.: 0 Cov.: 30 AF XY: 0.0000426 AC XY: 3 AN XY: 70418

African (AFR) AF: 0.00 AC: 0 AN: 37574

American (AMR) AF: 0.00 AC: 0 AN: 14600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.000783 AC: 4 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66250

Other (OTH) AF: 0.00 AC: 0 AN: 1976

Alfa AF: 0.00 Hom.: 164

Bravo AF: 0.00000378

ExAC AF: 0.0000167 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.098
DANN	Benign	0.69
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.011
Sift	Benign	0.042	D
Sift4G	Benign	0.51	T
Polyphen		0.099	B
Vest4		0.16
MutPred		0.17		Loss of phosphorylation at S330 (P = 0.0059)
MVP		0.23
MPC		0.26
ClinPred		0.032	T
GERP RS		-2.2
PromoterAI		-0.0068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.12

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: rs34535433; hg19: chr17-55183813;