17-57106452-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_003488.4(AKAP1):​c.988A>G​(p.Ser330Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0662 in 143,616 control chromosomes in the GnomAD database, including 425 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (425 hom., cov: 30)
  • Exomes 𝑓: 0.036 (2525 hom.)
  • Failed GnomAD Quality Control
• Consequence: AKAP1 NM_003488.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015726388).
• BP6: Variant 17-57106452-A-G is Benign according to our data. Variant chr17-57106452-A-G is described in ClinVar as Benign. ClinVar VariationId is 770798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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>G	p.Ser330Gly	missense	Exon 2 of 11	NP_003479.1	A0A140VK05
	AKAP1	NM_001242902.2		c.988A>G	p.Ser330Gly	missense	Exon 3 of 12	NP_001229831.1	Q92667-1
	AKAP1	NM_001242903.2		c.988A>G	p.Ser330Gly	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>G	p.Ser330Gly	missense	Exon 2 of 11	ENSP00000337736.3	Q92667-1
	AKAP1	ENST00000314126.4	TSL:1	c.988A>G	p.Ser330Gly	missense	Exon 2 of 7	ENSP00000314075.3	Q92667-2
	AKAP1	ENST00000964437.1		c.988A>G	p.Ser330Gly	missense	Exon 2 of 12	ENSP00000634496.1

Frequencies

GnomAD3 genomes AF: 0.0663 AC: 9509 AN: 143500 Hom.: 425 Cov.: 30

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.0652

Gnomad ASJ AF: 0.0483

Gnomad EAS AF: 0.00628

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.0812

Gnomad MID AF: 0.0545

Gnomad NFE AF: 0.0930

Gnomad OTH AF: 0.0684

GnomAD2 exomes AF: 0.0243 AC: 5610 AN: 230600 AF XY: 0.0227

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00296

Gnomad FIN exome AF: 0.0335

Gnomad NFE exome AF: 0.0305

Gnomad OTH exome AF: 0.0312

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0357 AC: 45761 AN: 1282852 Hom.: 2525 Cov.: 34 AF XY: 0.0370 AC XY: 23669 AN XY: 640214

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0593 AC: 1796 AN: 30272

American (AMR) AF: 0.0293 AC: 1248 AN: 42630

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 872 AN: 24752

East Asian (EAS) AF: 0.0137 AC: 542 AN: 39538

South Asian (SAS) AF: 0.0403 AC: 3259 AN: 80964

European-Finnish (FIN) AF: 0.0882 AC: 4409 AN: 49990

Middle Eastern (MID) AF: 0.0292 AC: 158 AN: 5406

European-Non Finnish (NFE) AF: 0.0326 AC: 31086 AN: 954672

Other (OTH) AF: 0.0438 AC: 2391 AN: 54628

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0662 AC: 9503 AN: 143616 Hom.: 425 Cov.: 30 AF XY: 0.0645 AC XY: 4511 AN XY: 69940

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0224 AC: 841 AN: 37540

American (AMR) AF: 0.0651 AC: 945 AN: 14506

Ashkenazi Jewish (ASJ) AF: 0.0483 AC: 164 AN: 3396

East Asian (EAS) AF: 0.00629 AC: 32 AN: 5084

South Asian (SAS) AF: 0.0415 AC: 189 AN: 4554

European-Finnish (FIN) AF: 0.0812 AC: 814 AN: 10026

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0930 AC: 6085 AN: 65408

Other (OTH) AF: 0.0677 AC: 134 AN: 1980

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0763 Hom.: 164

TwinsUK AF: 0.104 AC: 385

ALSPAC AF: 0.103 AC: 397

ExAC AF: 0.00475 AC: 569

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.037
DANN	Benign	0.63
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.0
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.021
Sift	Benign	0.48	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.22
ClinPred		0.0010	T
GERP RS		-2.2
PromoterAI		0.0076	Neutral
Varity_R		0.059
gMVP		0.081
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV58470774; COSMIC: COSV58470774;