21-43418466-G-C

Variant names:

• chr21-43418466-G-C
• rs200402559
• NM_173354.5:c.1538C>G

Variant summary

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

The NM_173354.5(SIK1):​c.1538C>G​(p.Ala513Gly) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A513V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57
• Publications: 6 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=0.1616587).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173354.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK1	NM_173354.5	MANE Select	c.1538C>G	p.Ala513Gly	missense	Exon 12 of 14	NP_775490.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK1	ENST00000270162.8	TSL:1 MANE Select	c.1538C>G	p.Ala513Gly	missense	Exon 12 of 14	ENSP00000270162.6

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00000410 AC: 1 AN: 243818 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: 0.00000931

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 7408 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 3852

African (AFR) AF: 0.00 AC: 0 AN: 566

American (AMR) AF: 0.00 AC: 0 AN: 538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 296

East Asian (EAS) AF: 0.00 AC: 0 AN: 228

South Asian (SAS) AF: 0.00 AC: 0 AN: 914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 32

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4148

Other (OTH) AF: 0.00 AC: 0 AN: 496

GnomAD4 genome Cov.: 0

ExAC AF: 0.00000825 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Uncertain:1

Jun 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with glycine at codon 513 of the SIK1 protein (p.Ala513Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SIK1 protein function. ClinVar contains an entry for this variant (Variation ID: 938594). This variant has been observed in individual(s) with clinical features of SIK1-related conditions (Invitae). This variant is present in population databases (rs200402559, ExAC 0.002%).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.098
Sift	Benign	0.070	T
Sift4G	Benign	0.49	T
Polyphen		0.49	P
Vest4		0.12
MutPred		0.10		Gain of glycosylation at S512 (P = 0.0441)
MVP		0.51
MPC		0.44
ClinPred		0.77	D
GERP RS		4.5
Varity_R		0.084
gMVP		0.21
Mutation Taster		=72/28	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: rs200402559; hg19: chr21-44838346;