1-243613681-T-C

Position:

• chr1-243613681-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_005465.7(AKT3):​c.686A>G​(p.Asn229Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKT3 NM_005465.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 6.96

Genes affected

AKT3 (HGNC:393): (AKT serine/threonine kinase 3) The protein encoded by this gene is a member of the AKT, also called PKB, serine/threonine protein kinase family. AKT kinases are known to be regulators of cell signaling in response to insulin and growth factors. They are involved in a wide variety of biological processes including cell proliferation, differentiation, apoptosis, tumorigenesis, as well as glycogen synthesis and glucose uptake. This kinase has been shown to be stimulated by platelet-derived growth factor (PDGF), insulin, and insulin-like growth factor 1 (IGF1). Alternatively splice transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), AKT3. . Gene score misZ 3.946 (greater than the threshold 3.09). Trascript score misZ 4.2291 (greater than threshold 3.09). GenCC has associacion of gene with microcephaly, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1.
• PP5: Variant 1-243613681-T-C is Pathogenic according to our data. Variant chr1-243613681-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 39815.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-243613681-T-C is described in UniProt as null. Variant chr1-243613681-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKT3	NM_005465.7	c.686A>G	p.Asn229Ser	missense_variant	8/14	ENST00000673466.1	NP_005456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKT3	ENST00000673466.1	c.686A>G	p.Asn229Ser	missense_variant	8/14		NM_005465.7	ENSP00000500582	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2014	- -

Megalencephaly-capillary malformation-polymicrogyria syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

Department Of Pediatrics And Neonatology, Nagoya City University Graduate School Of Medical Sciences

Nov 01, 2015

Patient, a 3 year-old girl, showed severe developmental delay, hypotonia, seizure, and dysmorphic facial features. She had no meaningful words. Her last head circumference was 58 cm (+6.2SD). This mutation was confirmed de novo. The expression level of phosphorylated S6 ribosomal protein in her lymphoblastoid cell line was elevated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;.;D;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.67	D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.49	N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.96	D;D;D;D
Vest4		0.81
MutPred		0.52		Gain of phosphorylation at N229 (P = 0.1548);Gain of phosphorylation at N229 (P = 0.1548);Gain of phosphorylation at N229 (P = 0.1548);Gain of phosphorylation at N229 (P = 0.1548);
MVP		0.58
MPC		1.7
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.59
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514605; hg19: chr1-243776983;