7-92085597-C-T

Variant names:

• chr7-92085597-C-T
• rs1063242
• NM_005751.5:c.8935C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005751.5(AKAP9):​c.8935C>T​(p.Pro2979Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,614,044 control chromosomes in the GnomAD database, including 802,048 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 (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75657 hom., cov: 29)
  • Exomes 𝑓: 1.0 (726391 hom.)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.958
• Publications: 52 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.84979E-7).
• BP6: Variant 7-92085597-C-T is Benign according to our data. Variant chr7-92085597-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

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.8935C>T	p.Pro2979Ser	missense	Exon 36 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.8911C>T	p.Pro2971Ser	missense	Exon 36 of 50	NP_671714.1
	AKAP9	NM_001379277.1		c.3580C>T	p.Pro1194Ser	missense	Exon 15 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.8935C>T	p.Pro2979Ser	missense	Exon 36 of 50	ENSP00000348573.3
	AKAP9	ENST00000491695.2	TSL:1	c.3580C>T	p.Pro1194Ser	missense	Exon 15 of 29	ENSP00000494626.2
	AKAP9	ENST00000394534.7	TSL:1	c.2428C>T	p.Pro810Ser	missense	Exon 9 of 23	ENSP00000378042.3

Frequencies

GnomAD3 genomes AF: 0.997 AC: 151662 AN: 152136 Hom.: 75597 Cov.: 29

Gnomad AFR AF: 1.00

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.998

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.994

Gnomad FIN AF: 0.991

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.996

Gnomad OTH AF: 0.995

GnomAD2 exomes AF: 0.996 AC: 250346 AN: 251278 AF XY: 0.996

Gnomad AFR exome AF: 1.00

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.992

Gnomad NFE exome AF: 0.996

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.997 AC: 1457254 AN: 1461790 Hom.: 726391 Cov.: 43 AF XY: 0.996 AC XY: 724648 AN XY: 727202

African (AFR) AF: 0.999 AC: 33460 AN: 33478

American (AMR) AF: 0.998 AC: 44649 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 26093 AN: 26132

East Asian (EAS) AF: 1.00 AC: 39691 AN: 39692

South Asian (SAS) AF: 0.992 AC: 85542 AN: 86246

European-Finnish (FIN) AF: 0.992 AC: 52979 AN: 53406

Middle Eastern (MID) AF: 0.994 AC: 5732 AN: 5768

European-Non Finnish (NFE) AF: 0.997 AC: 1108886 AN: 1111956

Other (OTH) AF: 0.997 AC: 60222 AN: 60394

GnomAD4 genome AF: 0.997 AC: 151781 AN: 152254 Hom.: 75657 Cov.: 29 AF XY: 0.997 AC XY: 74211 AN XY: 74448

African (AFR) AF: 1.00 AC: 41518 AN: 41530

American (AMR) AF: 0.998 AC: 15259 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.998 AC: 3466 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5192 AN: 5192

South Asian (SAS) AF: 0.994 AC: 4782 AN: 4812

European-Finnish (FIN) AF: 0.991 AC: 10519 AN: 10612

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.996 AC: 67738 AN: 68034

Other (OTH) AF: 0.995 AC: 2101 AN: 2112

Alfa AF: 0.996 Hom.: 155881

Bravo AF: 0.998

TwinsUK AF: 0.999 AC: 3703

ALSPAC AF: 0.998 AC: 3846

ESP6500AA AF: 1.00 AC: 4405

ESP6500EA AF: 0.996 AC: 8567

ExAC AF: 0.996 AC: 120947

Asia WGS AF: 0.997 AC: 3469 AN: 3478

EpiCase AF: 0.996

EpiControl AF: 0.996

ClinVar

ClinVar submissions as Germline

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	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	0.057
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.2
DANN	Benign	0.63
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.081	T
MetaRNN	Benign	9.8e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.96
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	0.89	T
Vest4		0.024
MPC		0.053
ClinPred		0.0014	T
GERP RS		2.5
Varity_R		0.019
gMVP		0.047
Mutation Taster		=100/0	polymorphism (auto)

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: rs1063242; hg19: chr7-91714911; COSMIC: COSV104663065;