Genetic Variant AKT1S1:p.Asp238Asn (chr19-49869976-C-T) – 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.712G>A(p.Asp238Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D238H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AKT1S1
NM_001098633.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.24

Publications

1 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:

Genome browser will be placed here

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.712G>A	p.Asp238Asn	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.712G>A	p.Asp238Asn	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:

1391932

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

685230

African (AFR)

AF:

0.00

AC:

AN:

30670

American (AMR)

AF:

0.00

AC:

AN:

36750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24844

East Asian (EAS)

AF:

0.00

AC:

AN:

34634

South Asian (SAS)

AF:

0.00

AC:

AN:

78886

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5638

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074184

Other (OTH)

AF:

0.00

AC:

AN:

57492

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.072

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;D;D;D;D;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.90

D;.;.;.;.;D

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.52

D;D;D;D;D;D

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.0

M;M;M;M;M;.

PhyloP100

5.2

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.8

D;D;D;D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.015

D;D;D;D;D;D

Sift4G

Benign

0.51

T;T;T;T;T;T

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.67

MutPred

0.25

Gain of catalytic residue at D238 (P = 0.0119);Gain of catalytic residue at D238 (P = 0.0119);Gain of catalytic residue at D238 (P = 0.0119);Gain of catalytic residue at D238 (P = 0.0119);Gain of catalytic residue at D238 (P = 0.0119);.;

MVP

0.83

MPC

3.0

ClinPred

0.99

GERP RS

3.9

Varity_R

0.61

gMVP

0.24

Mutation Taster

=60/40

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over