7-92107395-T-G

Variant names:

• chr7-92107395-T-G
• rs145675748
• NM_005751.5:c.11519T>G

Variant summary

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

The NM_005751.5(AKAP9):​c.11519T>G​(p.Ile3840Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 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. I3840T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKAP9 NM_005751.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• Publications: 5 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKAP9	NM_005751.5	c.11519T>G	p.Ile3840Ser	missense_variant	Exon 48 of 50	ENST00000356239.8	NP_005742.4
AKAP9	NM_147185.3	c.11495T>G	p.Ile3832Ser	missense_variant	Exon 48 of 50		NP_671714.1
AKAP9	NM_001379277.1	c.6164T>G	p.Ile2055Ser	missense_variant	Exon 27 of 29		NP_001366206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKAP9	ENST00000356239.8	c.11519T>G	p.Ile3840Ser	missense_variant	Exon 48 of 50	1	NM_005751.5	ENSP00000348573.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251372 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	23
DANN	Benign	0.81
DEOGEN2	Benign	0.0	.;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.67	T;T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	.;.;.
PhyloP100		1.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.79	N;.;N
REVEL	Benign	0.062
Sift	Benign	0.45	T;.;T
Sift4G	Pathogenic	0.0	.;.;T
Vest4		0.28
ClinPred		0.11	T
GERP RS		4.4
Varity_R		0.034
gMVP		0.36
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145675748; hg19: chr7-91736709;