rs200402559

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr21-43418466-G-A
• chr21-43418466-G-C
• chr21-43418466-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_173354.5(SIK1):​c.1538C>T​(p.Ala513Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A513E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIK1 NM_173354.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.57

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]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016385317).
• BP6: Variant 21-43418466-G-A is Benign according to our data. Variant chr21-43418466-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 570345.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIK1	NM_173354.5	c.1538C>T	p.Ala513Val	missense_variant	Exon 12 of 14	ENST00000270162.8	NP_775490.2
SIK1	XM_011529474.3	c.1391C>T	p.Ala464Val	missense_variant	Exon 11 of 13		XP_011527776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIK1	ENST00000270162.8	c.1538C>T	p.Ala513Val	missense_variant	Exon 12 of 14	1	NM_173354.5	ENSP00000270162.6

Frequencies

GnomAD3 genomes AC: 0 AN: 0 Hom.: 0 Cov.: 0

GnomAD2 exomes AF: 0.000283 AC: 69 AN: 243818 AF XY: 0.000226

Gnomad AFR exome AF: 0.0000634

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.000503

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000135 AC: 1 AN: 7408 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 3852

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 566

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 538

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 296

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 228

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 914

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 190

Gnomad4 NFE exome AF: 0.000241 AC: 1 AN: 4148

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 496

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Alfa AF: 0.000161 Hom.: 0

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Developmental and epileptic encephalopathy, 30 Uncertain:1 Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SIK1 NM_173354.4 exon 12 p.Ala513Val (c.1538C>T): This variant has not been reported in the literature, but it is present in 0.2% (60/25748) of Finnish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/21-44838346-G-A). This variant amino acid, valine (Val), is present in one mammal and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant are insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.12
Sift	Benign	0.24	T
Sift4G	Benign	0.75	T
Polyphen		0.69	P
Vest4		0.094
MVP		0.50
MPC		0.14
ClinPred		0.046	T
GERP RS		4.5
Varity_R		0.063
gMVP		0.17
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200402559; hg19: chr21-44838346; COSMIC: COSV54257895; COSMIC: COSV54257895;