Genetic Variant AKT1S1:p.Pro242Ser (chr19-49869964-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001098633.4(AKT1S1):c.724C>T(p.Pro242Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AKT1S1
NM_001098633.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.54

Publications

0 publications found

Variant links:

Genes affected

AKT1S1 (HGNC:28426): (AKT1 substrate 1) AKT1S1 is a proline-rich substrate of AKT (MIM 164730) that binds 14-3-3 protein (see YWHAH, MIM 113508) when phosphorylated (Kovacina et al., 2003 [PubMed 12524439]).[supplied by OMIM, Mar 2008]

AKT1S1 links:

PNKP (HGNC:9154): (polynucleotide kinase 3'-phosphatase) This locus represents a gene involved in DNA repair. In response to ionizing radiation or oxidative damage, the protein encoded by this locus catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids. Mutations at this locus have been associated with microcephaly, seizures, and developmental delay.[provided by RefSeq, Sep 2010]

PNKP Gene-Disease associations (from GenCC):

ataxia - oculomotor apraxia type 4
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine
microcephaly, seizures, and developmental delay
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease type 2B2
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PNKP links:

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ACMG classification

Classification was made for transcript

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
AKT1S1	NM_001098633.4 link	c.724C>T	p.Pro242Ser	missense_variant	Exon 5 of 5	ENST00000344175.10	NP_001092103.1	Q96B36-1A0A024QZF6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1S1	ENST00000344175.10 link	c.724C>T	p.Pro242Ser	missense_variant	Exon 5 of 5	3	NM_001098633.4	ENSP00000341698.5		Q96B36-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1391016

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684608

African (AFR)

AF:

0.00

AC:

AN:

30662

American (AMR)

AF:

0.00

AC:

AN:

36838

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24808

East Asian (EAS)

AF:

0.00

AC:

AN:

34666

South Asian (SAS)

AF:

0.00

AC:

AN:

78730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1073200

Other (OTH)

AF:

0.00

AC:

AN:

57416

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.724C>T (p.P242S) alteration is located in exon 5 (coding exon 4) of the AKT1S1 gene. This alteration results from a C to T substitution at nucleotide position 724, causing the proline (P) at amino acid position 242 to be replaced by a serine (S). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;D;D;D;D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

D;.;.;.;.;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.54

D;D;D;D;D;D

MetaSVM

Benign

-0.32

MutationAssessor

Uncertain

2.3

M;M;M;M;M;.

PhyloP100

6.5

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-6.8

D;D;D;D;D;D

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.54

MutPred

0.41

Gain of phosphorylation at P242 (P = 0.0287);Gain of phosphorylation at P242 (P = 0.0287);Gain of phosphorylation at P242 (P = 0.0287);Gain of phosphorylation at P242 (P = 0.0287);Gain of phosphorylation at P242 (P = 0.0287);.;

MVP

0.80

MPC

3.1

ClinPred

1.0

GERP RS

3.9

Varity_R

0.93

gMVP

0.61

Mutation Taster

=30/70

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over