21-43420344-C-T

Variant names:

• chr21-43420344-C-T
• rs376891838
• NM_173354.5:c.862G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_173354.5(SIK1):​c.862G>A​(p.Ala288Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/24 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. A288S) 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: 0.0180
• 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)
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.862G>A	p.Ala288Thr	missense	Exon 8 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.862G>A	p.Ala288Thr	missense	Exon 8 of 14	ENSP00000270162.6	P57059
	SIK1	ENST00000880890.1		c.862G>A	p.Ala288Thr	missense	Exon 8 of 13	ENSP00000550949.1
	SIK1	ENST00000880889.1		c.862G>A	p.Ala288Thr	missense	Exon 8 of 13	ENSP00000550948.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247306 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: 0.00000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 504 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 278

African (AFR) AF: 0.00 AC: 0 AN: 16

American (AMR) AF: 0.00 AC: 0 AN: 60

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14

East Asian (EAS) AF: 0.00 AC: 0 AN: 10

South Asian (SAS) AF: 0.00 AC: 0 AN: 102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 276

Other (OTH) AF: 0.00 AC: 0 AN: 22

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.9
DANN	Benign	0.85
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L
PhyloP100		0.018
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.039
Sift	Benign	0.48	T
Sift4G	Benign	0.56	T
Polyphen		0.037	B
Vest4		0.086
MutPred		0.34		Gain of glycosylation at A288 (P = 0.0254)
MVP		0.38
MPC		0.13
ClinPred		0.033	T
GERP RS		-8.2
Varity_R		0.030
gMVP		0.20
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: -26

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

Other links and lift over

dbSNP: rs376891838; hg19: chr21-44840224; COSMIC: COSV54259700; COSMIC: COSV54259700;