7-91992989-G-C

Variant names:

• chr7-91992989-G-C
• rs144888041
• NM_005751.5:c.510G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005751.5(AKAP9):​c.510G>C​(p.Glu170Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,614,098 control chromosomes in the GnomAD database, including 12 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E170V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (11 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 0.150
• Publications: 10 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047680736).
• BP6: Variant 7-91992989-G-C is Benign according to our data. Variant chr7-91992989-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190518.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.510G>C	p.Glu170Asp	missense	Exon 5 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.510G>C	p.Glu170Asp	missense	Exon 5 of 50	NP_671714.1	Q99996-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.510G>C	p.Glu170Asp	missense	Exon 5 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000394564.5	TSL:1	n.684G>C		non_coding_transcript_exon	Exon 5 of 7
	AKAP9	ENST00000359028.7	TSL:5	c.510G>C	p.Glu170Asp	missense	Exon 5 of 51	ENSP00000351922.4	A0A0A0MRF6

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 317 AN: 152158 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00191 AC: 481 AN: 251328 AF XY: 0.00174

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00264

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00277 AC: 4054 AN: 1461822 Hom.: 11 Cov.: 31 AF XY: 0.00265 AC XY: 1925 AN XY: 727214

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00420 AC: 188 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86256

European-Finnish (FIN) AF: 0.000468 AC: 25 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00328 AC: 3643 AN: 1111964

Other (OTH) AF: 0.00270 AC: 163 AN: 60388

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152276 Hom.: 1 Cov.: 31 AF XY: 0.00197 AC XY: 147 AN XY: 74458

African (AFR) AF: 0.000505 AC: 21 AN: 41554

American (AMR) AF: 0.00445 AC: 68 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00232 Hom.: 0

Bravo AF: 0.00234

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00180 AC: 218

EpiCase AF: 0.00224

EpiControl AF: 0.00320

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	3	not specified (3)
-	-	1	Brugada syndrome 1 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Catecholaminergic polymorphic ventricular tachycardia (1)
-	1	-	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)
-	-	1	Long QT syndrome 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.0095
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.15
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.043
Sift	Benign	0.15	T
Sift4G	Benign	0.23	T
Polyphen		0.058	B
Vest4		0.40
MutPred		0.10		Gain of loop (P = 0.024)
MVP		0.43
MPC		0.086
ClinPred		0.011	T
GERP RS		4.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.062
gMVP		0.20
Mutation Taster		=99/1	polymorphism

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: rs144888041; hg19: chr7-91622303; COSMIC: COSV99072576;