rs35359994

Variant names:

• chr17-57106431-G-A
• rs35359994
• NM_003488.4:c.967G>A

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.967G>A​(p.Gly323Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0355 in 1,437,222 control chromosomes in the GnomAD database, including 2,678 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 0.061 (374 hom., cov: 31)
  • Exomes 𝑓: 0.033 (2304 hom.)
• Consequence: AKAP1 NM_003488.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22
• Publications: 16 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=0.0014906526).
• BP6: Variant 17-57106431-G-A is Benign according to our data. Variant chr17-57106431-G-A is described in ClinVar as Benign. ClinVar VariationId is 770797.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.967G>A	p.Gly323Ser	missense	Exon 2 of 11	NP_003479.1
	AKAP1	NM_001242902.2		c.967G>A	p.Gly323Ser	missense	Exon 3 of 12	NP_001229831.1
	AKAP1	NM_001242903.2		c.967G>A	p.Gly323Ser	missense	Exon 3 of 12	NP_001229832.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP1	ENST00000337714.8	TSL:1 MANE Select	c.967G>A	p.Gly323Ser	missense	Exon 2 of 11	ENSP00000337736.3
	AKAP1	ENST00000314126.4	TSL:1	c.967G>A	p.Gly323Ser	missense	Exon 2 of 7	ENSP00000314075.3
	AKAP1	ENST00000964437.1		c.967G>A	p.Gly323Ser	missense	Exon 2 of 12	ENSP00000634496.1

Frequencies

GnomAD3 genomes AF: 0.0608 AC: 8834 AN: 145222 Hom.: 374 Cov.: 31

Gnomad AFR AF: 0.0196

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.0633

Gnomad ASJ AF: 0.0437

Gnomad EAS AF: 0.00603

Gnomad SAS AF: 0.0436

Gnomad FIN AF: 0.0818

Gnomad MID AF: 0.0455

Gnomad NFE AF: 0.0858

Gnomad OTH AF: 0.0668

GnomAD2 exomes AF: 0.0202 AC: 4643 AN: 230220 AF XY: 0.0198

Gnomad AFR exome AF: 0.00656

Gnomad AMR exome AF: 0.0194

Gnomad ASJ exome AF: 0.00952

Gnomad EAS exome AF: 0.00306

Gnomad FIN exome AF: 0.0220

Gnomad NFE exome AF: 0.0270

Gnomad OTH exome AF: 0.0298

GnomAD4 exome AF: 0.0326 AC: 42173 AN: 1291882 Hom.: 2304 Cov.: 34 AF XY: 0.0340 AC XY: 21888 AN XY: 644010

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

African (AFR) AF: 0.00906 AC: 294 AN: 32442

American (AMR) AF: 0.0263 AC: 1127 AN: 42858

Ashkenazi Jewish (ASJ) AF: 0.0336 AC: 833 AN: 24806

East Asian (EAS) AF: 0.0136 AC: 539 AN: 39560

South Asian (SAS) AF: 0.0395 AC: 3204 AN: 81170

European-Finnish (FIN) AF: 0.0835 AC: 4162 AN: 49868

Middle Eastern (MID) AF: 0.0255 AC: 138 AN: 5414

European-Non Finnish (NFE) AF: 0.0309 AC: 29691 AN: 960614

Other (OTH) AF: 0.0396 AC: 2185 AN: 55150

⚠️ 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: 0.0607 AC: 8829 AN: 145340 Hom.: 374 Cov.: 31 AF XY: 0.0597 AC XY: 4233 AN XY: 70924

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

African (AFR) AF: 0.0195 AC: 784 AN: 40130

American (AMR) AF: 0.0632 AC: 923 AN: 14600

Ashkenazi Jewish (ASJ) AF: 0.0437 AC: 147 AN: 3366

East Asian (EAS) AF: 0.00604 AC: 31 AN: 5132

South Asian (SAS) AF: 0.0430 AC: 198 AN: 4608

European-Finnish (FIN) AF: 0.0818 AC: 818 AN: 10006

Middle Eastern (MID) AF: 0.0417 AC: 12 AN: 288

European-Non Finnish (NFE) AF: 0.0858 AC: 5528 AN: 64426

Other (OTH) AF: 0.0661 AC: 132 AN: 1998

⚠️ 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: 0.0902 Hom.: 172

Bravo AF: 0.0758

TwinsUK AF: 0.104 AC: 385

ALSPAC AF: 0.104 AC: 399

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.0706 AC: 607

ExAC AF: 0.0730 AC: 8826

ClinVar

ClinVar submissions as Germline

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	0.080
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.3
DANN	Benign	0.72
DEOGEN2	Benign	0.094	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0076	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.014
Sift	Benign	0.21	T
Sift4G	Benign	0.23	T
Polyphen		0.023	B
Vest4		0.029
MPC		0.23
ClinPred		0.0015	T
GERP RS		-0.28
PromoterAI		-0.0038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.11
Mutation Taster		=99/1	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: rs35359994; hg19: chr17-55183792; COSMIC: COSV58473107; COSMIC: COSV58473107;