chr1-243613681-T-C

Position:

• chr1-243613681-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N229H) has been classified as Likely pathogenic.

• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Protein kinase (size 257) in uniprot entity AKT3_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_005465.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-243613682-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1518305.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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	ENSP00000500582.1

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
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;