chr14-32545971-G-A

Position:

• chr14-32545971-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004274.5(AKAP6):​c.1318G>A​(p.Val440Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AKAP6 NM_004274.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.18

Genes affected

AKAP6 (HGNC:376): (A-kinase anchoring protein 6) 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. The encoded protein is highly expressed in various brain regions and cardiac and skeletal muscle. It is specifically localized to the sarcoplasmic reticulum and nuclear membrane, and is involved in anchoring PKA to the nuclear membrane or sarcoplasmic reticulum. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17954984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKAP6	NM_004274.5	c.1318G>A	p.Val440Ile	missense_variant	4/14	ENST00000280979.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKAP6	ENST00000280979.9	c.1318G>A	p.Val440Ile	missense_variant	4/14	1	NM_004274.5	P1
AKAP6	ENST00000557354.5	c.1318G>A	p.Val440Ile	missense_variant	4/10	1
AKAP6	ENST00000557272.1	c.1318G>A	p.Val440Ile	missense_variant	4/13	5
AKAP6	ENST00000553547.5	c.592G>A	p.Val198Ile	missense_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

The c.1318G>A (p.V440I) alteration is located in exon 4 (coding exon 3) of the AKAP6 gene. This alteration results from a G to A substitution at nucleotide position 1318, causing the valine (V) at amino acid position 440 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T;.;.;.
Eigen	Benign	0.010
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.3	M;M;.;.
MutationTaster	Benign	0.92	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.63	N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.045	D;T;D;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.26	B;.;.;.
Vest4		0.030
MutPred		0.25		Gain of catalytic residue at L439 (P = 0);Gain of catalytic residue at L439 (P = 0);Gain of catalytic residue at L439 (P = 0);.;
MVP		0.52
MPC		0.050
ClinPred		0.45	T
GERP RS		4.8
Varity_R		0.077
gMVP		0.083

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-33015177;