chr7-92080019-T-A

Variant names:

• chr7-92080019-T-A
• rs199909093
• NM_005751.5:c.7886T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005751.5(AKAP9):​c.7886T>A​(p.Val2629Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2629A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.02
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16826719).

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.7886T>A	p.Val2629Glu	missense	Exon 31 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.7862T>A	p.Val2621Glu	missense	Exon 31 of 50	NP_671714.1
	AKAP9	NM_001379277.1		c.2531T>A	p.Val844Glu	missense	Exon 10 of 29	NP_001366206.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.7886T>A	p.Val2629Glu	missense	Exon 31 of 50	ENSP00000348573.3
	AKAP9	ENST00000491695.2	TSL:1	c.2531T>A	p.Val844Glu	missense	Exon 10 of 29	ENSP00000494626.2
	AKAP9	ENST00000394534.7	TSL:1	c.1379T>A	p.Val460Glu	missense	Exon 4 of 23	ENSP00000378042.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410104 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 699490

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

African (AFR) AF: 0.0000326 AC: 1 AN: 30656

American (AMR) AF: 0.00 AC: 0 AN: 30196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39302

South Asian (SAS) AF: 0.00 AC: 0 AN: 76252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095760

Other (OTH) AF: 0.00 AC: 0 AN: 57980

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.054
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.16	T
Vest4		0.38
MVP		0.37
MPC		0.37
ClinPred		0.89	D
GERP RS		3.5
Varity_R		0.28
gMVP		0.40
Mutation Taster		=91/9	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: rs199909093; hg19: chr7-91709333;