NM_005751.5:c.10840A>G

Variant names:

• chr7-92099813-A-G
• rs34327395
• NM_005751.5:c.10840A>G

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.10840A>G​(p.Met3614Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00942 in 1,614,124 control chromosomes in the GnomAD database, including 101 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. M3614K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0090 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (93 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.90
• Publications: 16 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]

CYP51A1 (HGNC:2649): (cytochrome P450 family 51 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This endoplasmic reticulum protein participates in the synthesis of cholesterol by catalyzing the removal of the 14alpha-methyl group from lanosterol. Homologous genes are found in all three eukaryotic phyla, fungi, plants, and animals, suggesting that this is one of the oldest cytochrome P450 genes. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

CYP51A1 Gene-Disease associations (from GenCC):

• cataract

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056039095).
• BP6: Variant 7-92099813-A-G is Benign according to our data. Variant chr7-92099813-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 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.10840A>G	p.Met3614Val	missense	Exon 44 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.10816A>G	p.Met3606Val	missense	Exon 44 of 50	NP_671714.1	Q99996-3
	AKAP9	NM_001379277.1		c.5485A>G	p.Met1829Val	missense	Exon 23 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.10840A>G	p.Met3614Val	missense	Exon 44 of 50	ENSP00000348573.3	Q99996-2
	AKAP9	ENST00000491695.2	TSL:1	c.5485A>G	p.Met1829Val	missense	Exon 23 of 29	ENSP00000494626.2	A0A2R8Y590
	AKAP9	ENST00000394534.7	TSL:1	c.3832A>G	p.Met1278Val	missense	Exon 17 of 23	ENSP00000378042.3	H7BYL6

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1378 AN: 152206 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00854

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00703 AC: 1767 AN: 251372 AF XY: 0.00721

Gnomad AFR exome AF: 0.00892

Gnomad AMR exome AF: 0.00543

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00930

GnomAD4 exome AF: 0.00945 AC: 13819 AN: 1461800 Hom.: 93 Cov.: 31 AF XY: 0.00945 AC XY: 6870 AN XY: 727210

African (AFR) AF: 0.00732 AC: 245 AN: 33478

American (AMR) AF: 0.00572 AC: 256 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00930 AC: 243 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00281 AC: 242 AN: 86256

European-Finnish (FIN) AF: 0.00144 AC: 77 AN: 53412

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5768

European-Non Finnish (NFE) AF: 0.0109 AC: 12141 AN: 1111942

Other (OTH) AF: 0.00916 AC: 553 AN: 60392

GnomAD4 genome AF: 0.00905 AC: 1378 AN: 152324 Hom.: 8 Cov.: 32 AF XY: 0.00831 AC XY: 619 AN XY: 74492

African (AFR) AF: 0.00851 AC: 354 AN: 41580

American (AMR) AF: 0.0111 AC: 170 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

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

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 755 AN: 68036

Other (OTH) AF: 0.0171 AC: 36 AN: 2110

Alfa AF: 0.0100 Hom.: 35

Bravo AF: 0.0101

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.00717 AC: 871

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00992

EpiControl AF: 0.0122

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)
-	-	2	not provided (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Congenital long QT syndrome (1)
-	-	1	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.63
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.90	T
PhyloP100		2.9
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.042
Sift	Benign	0.27	T
Sift4G	Benign	0.45	T
Vest4		0.28
MVP		0.21
MPC		0.080
ClinPred		0.014	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.16
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: rs34327395; hg19: chr7-91729127; COSMIC: COSV99072410; COSMIC: COSV99072410;