21-43416836-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_173354.5(SIK1):​c.2258C>A​(p.Ala753Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 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. A753S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Consequence

SIK1
NM_173354.5 missense

Scores

4
15

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.52

Publications

0 publications found
Variant links:
Genes affected
SIK1 (HGNC:11142): (salt inducible kinase 1) This gene encodes a serine/threonine protein kinase that contains a ubiquitin-associated (UBA) domain. The encoded protein is a member of the adenosine monophosphate-activated kinase (AMPK) subfamily of kinases that play a role in conserved signal transduction pathways. A mutation in this gene is associated with early infantile epileptic encephalopathy 30. [provided by RefSeq, Nov 2016]
SIK1 Gene-Disease associations (from GenCC):
  • developmental and epileptic encephalopathy, 30
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
  • early myoclonic encephalopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • genetic developmental and epileptic encephalopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • infantile spasms
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • generalized epilepsy
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13853958).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SIK1NM_173354.5 linkc.2258C>A p.Ala753Asp missense_variant Exon 14 of 14 ENST00000270162.8 NP_775490.2 P57059
SIK1XM_011529474.3 linkc.2111C>A p.Ala704Asp missense_variant Exon 13 of 13 XP_011527776.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SIK1ENST00000270162.8 linkc.2258C>A p.Ala753Asp missense_variant Exon 14 of 14 1 NM_173354.5 ENSP00000270162.6 P57059

Frequencies

GnomAD3 genomes
Cov.:
0
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
238546
AF XY:
0.00
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
0
GnomAD4 genome
Cov.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.095
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.092
T
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.088
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.47
T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.14
T
MetaSVM
Benign
-0.86
T
MutationAssessor
Benign
0.69
N
PhyloP100
3.5
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.39
N
REVEL
Benign
0.070
Sift
Uncertain
0.015
D
Sift4G
Benign
0.12
T
Polyphen
0.31
B
Vest4
0.12
MutPred
0.20
Gain of sheet (P = 0.0266);
MVP
0.18
MPC
0.24
ClinPred
0.40
T
GERP RS
4.9
Varity_R
0.18
gMVP
0.55
Mutation Taster
=94/6
polymorphism

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

Other links and lift over

dbSNP: rs1444363139; hg19: chr21-44836716; API