chr21-43416822-G-A

Variant names:

• chr21-43416822-G-A
• rs2081033603
• NM_173354.5:c.2272C>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.2272C>T​(p.Pro758Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04
• Publications: 0 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.14483067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5	c.2272C>T	p.Pro758Ser	missense_variant	Exon 14 of 14	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3	c.2125C>T	p.Pro709Ser	missense_variant	Exon 13 of 13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8	c.2272C>T	p.Pro758Ser	missense_variant	Exon 14 of 14	1	NM_173354.5	ENSP00000270162.6

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Uncertain:1

Nov 18, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SIK1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 758 of the SIK1 protein (p.Pro758Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.067
Sift	Benign	0.055	T
Sift4G	Benign	0.079	T
Polyphen		0.44	B
Vest4		0.14
MutPred		0.41		Gain of relative solvent accessibility (P = 0.09);
MVP		0.32
MPC		0.17
ClinPred		0.079	T
GERP RS		4.0
Varity_R		0.037
gMVP		0.40
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs2081033603; hg19: chr21-44836702;