rs76177450

Variant names:

• chr7-92070953-T-C
• rs76177450
• NM_005751.5:c.6556T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005751.5(AKAP9):​c.6556T>C​(p.Ser2186Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,613,912 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. S2186C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (19 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.82
• Publications: 13 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005694568).
• BP6: Variant 7-92070953-T-C is Benign according to our data. Variant chr7-92070953-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 19 AD,AR gene

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.6556T>C	p.Ser2186Pro	missense	Exon 28 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.6532T>C	p.Ser2178Pro	missense	Exon 28 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.1201T>C	p.Ser401Pro	missense	Exon 7 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.6556T>C	p.Ser2186Pro	missense	Exon 28 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.1201T>C	p.Ser401Pro	missense	Exon 7 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000394534.7	TSL:1	c.49T>C	p.Ser17Pro	missense	Exon 1 of 23	ENSP00000378042.3	H7BYL6

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 151994 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00728

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00374

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00333 AC: 837 AN: 251434 AF XY: 0.00345

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00707

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00366 AC: 5354 AN: 1461802 Hom.: 19 Cov.: 31 AF XY: 0.00369 AC XY: 2680 AN XY: 727206

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.000917 AC: 41 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00227 AC: 196 AN: 86256

European-Finnish (FIN) AF: 0.00762 AC: 407 AN: 53414

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.00405 AC: 4503 AN: 1111950

Other (OTH) AF: 0.00295 AC: 178 AN: 60394

GnomAD4 genome AF: 0.00247 AC: 375 AN: 152110 Hom.: 1 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74368

African (AFR) AF: 0.000458 AC: 19 AN: 41498

American (AMR) AF: 0.000786 AC: 12 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00728 AC: 77 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00374 AC: 254 AN: 67988

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00343 Hom.: 4

Bravo AF: 0.00202

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00377 AC: 458

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Long QT syndrome 11 (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.8
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.058
Sift	Benign	0.28	T
Sift4G	Benign	0.79	T
Vest4		0.27
MVP		0.30
MPC		0.088
ClinPred		0.012	T
GERP RS		3.2
PromoterAI		0.022	Neutral
Varity_R		0.084
gMVP		0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76177450; hg19: chr7-91700267;