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. 16/22 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
• 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)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, PanelApp Australia
• early myoclonic 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 -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 VariationId is 570345.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK1	NM_173354.5	MANE Select	c.1538C>T	p.Ala513Val	missense	Exon 12 of 14	NP_775490.2	P57059

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIK1	ENST00000270162.8	TSL:1 MANE Select	c.1538C>T	p.Ala513Val	missense	Exon 12 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880890.1		c.1391C>T	p.Ala464Val	missense	Exon 11 of 13	ENSP00000550949.1
	SIK1	ENST00000880889.1		c.1462+555C>T		intron	N/A	ENSP00000550948.1

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

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: 0.000241 AC: 1 AN: 4148

Other (OTH) 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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Developmental and epileptic encephalopathy, 30 (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.6
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

Other links and lift over

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