rs6960867

Variant names:

• chr7-92083384-A-G
• rs6960867
• NM_005751.5:c.8375A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-92083384-A-G
• chr7-92083384-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005751.5(AKAP9):​c.8375A>G​(p.Asn2792Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,613,262 control chromosomes in the GnomAD database, including 116,125 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N2792H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (9247 hom., cov: 32)
  • Exomes 𝑓: 0.38 (106878 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.334
• Publications: 63 publications found

Genes affected

AKAP9 (HGNC:379): (A-kinase anchoring protein 9) 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. Alternate splicing of this gene results in at least two isoforms that localize to the centrosome and the Golgi apparatus, and interact with numerous signaling proteins from multiple signal transduction pathways. These signaling proteins include type II protein kinase A, serine/threonine kinase protein kinase N, protein phosphatase 1, protein phosphatase 2a, protein kinase C-epsilon and phosphodiesterase 4D3. [provided by RefSeq, Aug 2008]

AKAP9 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
• long QT syndrome 11

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.6543946E-4).
• BP6: Variant 7-92083384-A-G is Benign according to our data. Variant chr7-92083384-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005751.5. 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
	AKAP9	NM_005751.5	MANE Select	c.8375A>G	p.Asn2792Ser	missense	Exon 33 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.8351A>G	p.Asn2784Ser	missense	Exon 33 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.3020A>G	p.Asn1007Ser	missense	Exon 12 of 29	NP_001366206.1	A0A2R8Y590

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.8375A>G	p.Asn2792Ser	missense	Exon 33 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.3020A>G	p.Asn1007Ser	missense	Exon 12 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000394534.7	TSL:1	c.1868A>G	p.Asn623Ser	missense	Exon 6 of 23	ENSP00000378042.3	H7BYL6

Frequencies

GnomAD3 genomes AF: 0.340 AC: 51609 AN: 151960 Hom.: 9249 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.359 AC: 89641 AN: 249908 AF XY: 0.366

Gnomad AFR exome AF: 0.249

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.546

Gnomad EAS exome AF: 0.171

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.383

GnomAD4 exome AF: 0.379 AC: 553710 AN: 1461184 Hom.: 106878 Cov.: 42 AF XY: 0.380 AC XY: 276338 AN XY: 726924

African (AFR) AF: 0.248 AC: 8294 AN: 33464

American (AMR) AF: 0.301 AC: 13476 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 14132 AN: 26132

East Asian (EAS) AF: 0.185 AC: 7330 AN: 39672

South Asian (SAS) AF: 0.389 AC: 33550 AN: 86250

European-Finnish (FIN) AF: 0.387 AC: 20608 AN: 53286

Middle Eastern (MID) AF: 0.418 AC: 2412 AN: 5768

European-Non Finnish (NFE) AF: 0.388 AC: 431254 AN: 1111520

Other (OTH) AF: 0.375 AC: 22654 AN: 60376

GnomAD4 genome AF: 0.339 AC: 51620 AN: 152078 Hom.: 9247 Cov.: 32 AF XY: 0.339 AC XY: 25231 AN XY: 74346

African (AFR) AF: 0.251 AC: 10423 AN: 41478

American (AMR) AF: 0.338 AC: 5161 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1884 AN: 3472

East Asian (EAS) AF: 0.173 AC: 892 AN: 5166

South Asian (SAS) AF: 0.385 AC: 1858 AN: 4820

European-Finnish (FIN) AF: 0.386 AC: 4077 AN: 10566

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26222 AN: 67980

Other (OTH) AF: 0.368 AC: 776 AN: 2110

Alfa AF: 0.373 Hom.: 28077

Bravo AF: 0.331

TwinsUK AF: 0.377 AC: 1397

ALSPAC AF: 0.392 AC: 1511

ESP6500AA AF: 0.268 AC: 1180

ESP6500EA AF: 0.401 AC: 3451

ExAC AF: 0.359 AC: 43538

Asia WGS AF: 0.294 AC: 1026 AN: 3478

EpiCase AF: 0.392

EpiControl AF: 0.402

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Long QT syndrome 11 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.0
DANN	Benign	0.81
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.00057	T
MetaSVM	Benign	-0.92	T
PhyloP100		0.33
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.070
Sift	Benign	0.23	T
Sift4G	Benign	0.87	T
Vest4		0.061
MPC		0.046
ClinPred		0.0056	T
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.078
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: rs6960867; hg19: chr7-91712698; COSMIC: COSV62339152; COSMIC: COSV62339152;