rs376950905

Variant names:

• chr7-92065299-C-T
• rs376950905
• NM_005751.5:c.6046C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-92065299-C-T
• chr7-92065299-C-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_005751.5(AKAP9):​c.6046C>T​(p.Arg2016Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,612,618 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. 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. R2016H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.728
• Publications: 3 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015661955).
• BP6: Variant 7-92065299-C-T is Benign according to our data. Variant chr7-92065299-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 417028.

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.6046C>T	p.Arg2016Cys	missense	Exon 25 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.6046C>T	p.Arg2016Cys	missense	Exon 25 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.691C>T	p.Arg231Cys	missense	Exon 4 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.6046C>T	p.Arg2016Cys	missense	Exon 25 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.691C>T	p.Arg231Cys	missense	Exon 4 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000359028.7	TSL:5	c.6142C>T	p.Arg2048Cys	missense	Exon 26 of 51	ENSP00000351922.4	A0A0A0MRF6

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151834 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000176 AC: 44 AN: 250668 AF XY: 0.000148

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1460666 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 726698

African (AFR) AF: 0.0000598 AC: 2 AN: 33424

American (AMR) AF: 0.000850 AC: 38 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.0000760 AC: 3 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111326

Other (OTH) AF: 0.0000663 AC: 4 AN: 60330

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151952 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.000328 AC: 5 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3472

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.82
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.055	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.73
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.039
Sift	Benign	0.10	T
Sift4G	Benign	0.13	T
Vest4		0.15
MVP		0.26
MPC		0.069
ClinPred		0.038	T
GERP RS		0.63
Varity_R		0.12
gMVP		0.15
Mutation Taster		=89/11	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: rs376950905; hg19: chr7-91694613;