Genetic Variant AKT1S1:p.Ser88Gly (chr19-49873034-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001098633.4(AKT1S1):c.262A>G(p.Ser88Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,408,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S88C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

AKT1S1
NM_001098633.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.866

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.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity AKTS1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12958995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1S1	NM_001098633.4 link	c.262A>G	p.Ser88Gly	missense_variant	Exon 2 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.262A>G	p.Ser88Gly	missense_variant	Exon 2 of 5	3	NM_001098633.4	ENSP00000341698.5		Q96B36-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000284

AC:

AN:

1408948

Hom.:

Cov.:

AF XY:

0.00000287

AC XY:

AN XY:

696192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32102

American (AMR)

AF:

0.00

AC:

AN:

37028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25172

East Asian (EAS)

AF:

0.00

AC:

AN:

36616

South Asian (SAS)

AF:

0.00

AC:

AN:

79970

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5504

European-Non Finnish (NFE)

AF:

0.00000368

AC:

AN:

1085658

Other (OTH)

AF:

0.00

AC:

AN:

58422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.20

T;T;T;T;T;.;.

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.69

T;.;.;.;.;T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.13

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;L;L;L;.;.

PhyloP100

0.87

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.3

N;N;N;N;N;N;N

REVEL

Benign

0.049

Sift

Benign

0.092

T;T;T;T;T;T;T

Sift4G

Benign

0.13

T;T;T;T;T;T;.

Polyphen

0.0

B;B;B;B;B;.;.

Vest4

0.20

MutPred

0.26

Loss of glycosylation at S88 (P = 5e-04);Loss of glycosylation at S88 (P = 5e-04);Loss of glycosylation at S88 (P = 5e-04);Loss of glycosylation at S88 (P = 5e-04);Loss of glycosylation at S88 (P = 5e-04);.;Loss of glycosylation at S88 (P = 5e-04);

MVP

0.50

MPC

0.24

ClinPred

0.052

GERP RS

2.0

Varity_R

0.046

gMVP

0.11

Mutation Taster

=82/18

polymorphism

(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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19-49873034-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over