rs34956633

Variant names:

• chr7-92097290-A-G
• rs34956633
• NM_005751.5:c.10331A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000356239.8(AKAP9):​c.10331A>G​(p.Gln3444Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,613,946 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts 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. Q3444H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (72 hom.)
• Consequence: AKAP9 ENST00000356239.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.91
• Publications: 10 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=0.0038442016).
• BP6: Variant 7-92097290-A-G is Benign according to our data. Variant chr7-92097290-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 191556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0138 (2109/152376) while in subpopulation AFR AF = 0.0473 (1966/41590). AF 95% confidence interval is 0.0455. There are 44 homozygotes in GnomAd4. There are 983 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000356239.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	NM_005751.5	MANE Select	c.10331A>G	p.Gln3444Arg	missense	Exon 41 of 50	NP_005742.4
	AKAP9	NM_147185.3		c.10307A>G	p.Gln3436Arg	missense	Exon 41 of 50	NP_671714.1
	AKAP9	NM_001379277.1		c.4976A>G	p.Gln1659Arg	missense	Exon 20 of 29	NP_001366206.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKAP9	ENST00000356239.8	TSL:1 MANE Select	c.10331A>G	p.Gln3444Arg	missense	Exon 41 of 50	ENSP00000348573.3
	AKAP9	ENST00000491695.2	TSL:1	c.4976A>G	p.Gln1659Arg	missense	Exon 20 of 29	ENSP00000494626.2
	AKAP9	ENST00000394534.7	TSL:1	c.3391-296A>G		intron	N/A	ENSP00000378042.3

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2101 AN: 152258 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00369 AC: 912 AN: 246960 AF XY: 0.00283

Gnomad AFR exome AF: 0.0491

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000262

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.00158 AC: 2303 AN: 1461570 Hom.: 72 Cov.: 32 AF XY: 0.00140 AC XY: 1017 AN XY: 727060

African (AFR) AF: 0.0501 AC: 1676 AN: 33478

American (AMR) AF: 0.00304 AC: 136 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.000149 AC: 166 AN: 1111978

Other (OTH) AF: 0.00397 AC: 240 AN: 60394

GnomAD4 genome AF: 0.0138 AC: 2109 AN: 152376 Hom.: 44 Cov.: 32 AF XY: 0.0132 AC XY: 983 AN XY: 74522

African (AFR) AF: 0.0473 AC: 1966 AN: 41590

American (AMR) AF: 0.00483 AC: 74 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68036

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00474 Hom.: 61

Bravo AF: 0.0156

ESP6500AA AF: 0.0382 AC: 168

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00428 AC: 520

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000297

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Long QT syndrome 11 (2)
-	-	2	not specified (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	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.057
Sift	Benign	0.14	T
Sift4G	Benign	0.094	T
Vest4		0.46
MVP		0.42
MPC		0.36
ClinPred		0.012	T
GERP RS		4.3
PromoterAI		0.065	Neutral
Varity_R		0.085
gMVP		0.30
Mutation Taster		=94/6	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: rs34956633; hg19: chr7-91726604;