21-43418533-C-T

Variant names:

• chr21-43418533-C-T
• rs140222760
• NM_173354.5:c.1471G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_173354.5(SIK1):​c.1471G>A​(p.Val491Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 17/22 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. V491L) 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: -0.0810
• Publications: 1 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053058833).

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.1471G>A	p.Val491Ile	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.1471G>A	p.Val491Ile	missense	Exon 12 of 14	ENSP00000270162.6

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000249 AC: 6 AN: 241162 AF XY: 0.0000304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 2988 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1608

African (AFR) AF: 0.00 AC: 0 AN: 126

American (AMR) AF: 0.00 AC: 0 AN: 422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 58

East Asian (EAS) AF: 0.00 AC: 0 AN: 74

South Asian (SAS) AF: 0.00 AC: 0 AN: 564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1548

Other (OTH) AF: 0.00 AC: 0 AN: 146

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000284 Hom.: 0

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Uncertain:1

Feb 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 491 of the SIK1 protein (p.Val491Ile). This variant is present in population databases (rs140222760, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with SIK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1427786). 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 with a negative predictive value of 95%. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.88
DANN	Benign	0.79
DEOGEN2	Benign	0.089	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.23	N
PhyloP100		-0.081
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.059
Sift	Benign	0.62	T
Sift4G	Benign	0.98	T
Polyphen		0.0070	B
Vest4		0.063
MutPred		0.18		Gain of catalytic residue at P493 (P = 0.0595)
MVP		0.10
MPC		0.11
ClinPred		0.013	T
GERP RS		-2.1
Varity_R		0.020
gMVP		0.086
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140222760; hg19: chr21-44838413; COSMIC: COSV54258916; COSMIC: COSV54258916;